Industry Brief

Most Common Reasons

for FDA Form 483
Observations and Warning
Letters in Medical Device
Environments

“CDRH’s premarket and
postmarket programme
functions along product
lines, allowing our
experts to leverage their
knowledge to optimise
decision-making across
the product life cycle.”
– Centre for Devices and
Radiological Health (CDRH)2
Most Common Reasons for FDA Form 483 Observations and Warning Letters in Medical Device
Environments
Industry Brief
Regulatory inspections conducted by the U.S. Food and Drug Administration
(FDA) are commonly followed by a list of observations noted during an audit.
Issues that are considered objectionable conditions or compliance violations by
FDA inspectors are itemised in a Form 483 or a warning letter. These notices
follow a standard process, beginning with an enumeration of specific findings,
follow-up instructions, a deadline for completing the follow-up instructions,
and potential consequences for failing to make the necessary corrections. Upon
receiving either type of notification, the company is obligated to acknowledge
receipt of the document and craft a detailed course of action for correcting the
infractions.
Regulatory violations that result in a Form 483 or warning letter commonly
involve one or all of the following deviations:
• Not having quality control procedures in a regulated area that conform to
FDA regulations.
• Having procedures that conform to FDA regulations, but not following
them.
• Having procedures that conform to FDA regulations and following them,
but not having adequate documentation to provide evidence of compliance.
Medical device quality system regulations are documented in 21 CFR Part
820.1 Overall, the regulations are driven by the agency’s commitment to ensure
timely patient access to high-quality, safe, and effective medical products. In
support of this objective, the FDA continues to make adjustments and updates
within its organisation in order to keep pace with an evolving industry.
In 2019, the Centre for Devices and Radiological Health (CDRH) underwent a
reorganisation. Rather than having different staff oversee devices at certain
stages, the staff specialises in particular products and work in teams to follow
devices throughout their entire life cycle. This transformation is a transition
to a more holistic, team-based approach to premarket review, postmarket
surveillance, and compliance that strengthens its focus on safety and
effectiveness throughout the entire life cycle of medical devices.2
By understanding the FDA’s updated approach to medical device regulation
and the information provided in this document about inspection observations,
medical device companies can more easily identify and mitigate compliance
issues.
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 Industry Brief

Top FDA Observations

The FDA’s Office of Regulatory Affairs (ORA) oversees all field activities,
including inspections and enforcement. During an inspection, ORA investigators
may observe conditions they deem to be objectionable or in violation of
regulatory requirements. Based on data compiled from 2017 through 2019,
the most common FDA observations that lead to a Form 483 or warning letter
involve the following processes:3

• Corrective action/preventive action (CAPA).

• Customer complaints.
• Purchasing controls (supplier management).
• Medical device reporting (MDR) procedures.
• Process validation.

Corrective Action/Preventive Action

Under the Quality System Regulation 21 CFR 820.100(a), manufacturers of
medical devices must establish and maintain corrective action/preventive
action (CAPA) procedures, including:

• Investigating the cause of nonconformities relating to products, processes,

and the quality system.
• Identifying the action(s) needed to correct and prevent recurrence of
nonconforming products or other quality issues.
• Verifying or validating a CAPA to ensure that it is effective and does not
adversely affect the finished device.
• Implementing and recording changes in methods and procedures needed
to correct and prevent identified quality problems.
• Ensuring that information related to quality problems or a nonconforming
product is disseminated to those directly responsible for assuring the
quality of the product or preventing problems.

Common practices for CAPA compliance include documenting procedures for

identifying, responding, and mitigating problems discovered during production
and in response to complaints. It’s important that this documentation is
complete, detailed, and easily accessible to inspectors.

CAPA issues noted in actual warning letters:

• Failure to follow a procedure where any employee discovering a quality
incident is required to initiate a corrective action.
• Firm did not initiate a CAPA in response to multiple complaints.
• No documentation exists explaining why a CAPA was not initiated upon
learning about a problem.

Most Common Reasons for FDA Form 483 Observations and Warning Letters in Medical Device 2
Environments

“Having manufacturing
and quality functionality
on the same platform
is critical to what we’re
doing. We can have our
SOPs, we can have our
corrective and preventive
actions (CAPAs), we can
have our complaints all
under one platform.”
– Eli Tuber, Process Manager,
Carestream Health5
Most Common Reasons for FDA Form 483 Observations and Warning Letters in Medical Device
Environments
Industry Brief
MasterControl CAPATM automates all CAPA tasks. It integrates with other
quality processes, such as document control, change control, audit, and
customer complaints, for a holistic approach to quality management. A CAPA
form can be launched from other processes or forms — which preserves data
integrity. Relevant data from a form will automatically be entered into the
CAPA form, reducing errors common with manually transferring data.
Customer Complaints
21 CFR 820.198(a) defines a complaint as any written, electronic, or oral
communication that alleges deficiencies related to the identity, quality,
durability, reliability, safety, effectiveness, or performance of a device after it is
released for distribution. For compliance, a medical device manufacturer must
maintain complaint files, as well as procedures for receiving, reviewing, and
evaluating complaints. Complaint handling procedures must ensure:
• All complaints are processed in a uniform and timely manner.
• Verbal complaints are documented and filed immediately upon receipt.
• Complaints are evaluated to determine whether the complaint represents
an event that must be reported to the FDA.
The regulation further requires that complaint files and procedures be
contained within a formally designated business unit.4
Complaint handling issues noted in actual warning letters:
• No standard operating procedures (SOPs) documented for complaint
handling.
• Failure to maintain complaint files.
• Failure to establish procedures and a designated business unit to receive,
review, and evaluate complaints.
• Complaint handling processes are not properly documented. For example,
documentation should include complaint data analysis, corrective actions,
effectiveness checks, and confirmation that corrective actions are
appropriate and effective.
MasterControl ComplaintsTM is a secure, centralised solution for receiving
customer complaints and storing all subsequent documentation pertaining to
the investigation and correction of problems. It integrates with CAPA and all
other quality processes on a single platform, enabling you to easily track all
complaint documents and processes from initiation to completion.
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 Industry Brief

Purchasing Controls (Supplier Management)

21 CFR 820.50 applies to purchasing controls. The regulations require
manufacturers to set up specific requirements, including requirements
specified in the Quality System Regulation (QSR) that suppliers, contractors,
and consultants must comply with. The manufacturer then must develop
policies and procedures for ensuring that all purchased products conform to
the requirements. The procedures detailed in the regulation include:

• Evaluate, document, and select potential suppliers based on their ability to

meet specified requirements — including quality requirements.
• Define the type and extent of control exercised over the products and
suppliers.
• Develop and document specific policies and procedures for change control.
• Establish and maintain supplier data, which clearly describes the specified
requirements.

Supply chains are becoming extensive and complex, which makes ensuring
a high level of quality throughout the supply chain and a product’s life cycle
challenging. Effectively monitoring and managing quality with outsourced
products and materials is important. Regulatory agencies do not perform
routine inspections of component manufacturers, so the burden of regulatory
compliance is on the sponsor company.6

Supplier issues noted in actual warning letters:

• No documentation of supplier evaluations.
• Inadequate requirements for suppliers, i.e., control over validated
processes; reliance on supplier self-assessments.
• Failure to evaluate potential contractors.
• Failure to clearly define the type and extent of control to be exercised over
suppliers.
• Continues to experience contamination problems from a supplier even
after implementing previous corrective actions. Firm has not implemented
procedures to adequately control the products from this supplier or to
inspect incoming products to detect contamination.

MasterControl Supplier ExcellenceTM unifies all supplier management

processes for a more holistic and streamlined approach to ensuring supplier
quality and compliance throughout the supply chain and product life cycle.

• Provides a formalised supplier performance scorecard for tracking and

evaluating supplier quality, performance, and regulatory compliance.
• Automates all tasks pertaining to supplier corrective action requests
(SCARs), including routing, notification, follow-up, escalation, and approval.

Most Common Reasons for FDA Form 483 Observations and Warning Letters in Medical Device 4
Environments
 Industry Brief

• Automatically tracks and stores supplier information from qualification,

audits, deviations, and CAPA to help identify and mitigate supplier risks
and supplier corrective actions.

Written Medical Device Reporting Procedures

21 CFR 803.17 states that manufacturers, user facilities, and importers of
medical devices must develop, maintain, and implement written medical device
reporting (MDR) procedures for internal systems that provide:

• Timely and effective identification, communication, and evaluation of

events that may be subject to MDR requirements.
• An assessment on when an event meets the criteria for MDR reporting.
• Timely transmission of complete medical device reports to manufacturers
or the FDA (or both, if required).

In addition, organisations must establish documentation and recordkeeping

requirements for:

• The information that was evaluated to determine whether an event was

reportable.
• All medical device reports and information submitted to manufacturers
and/or the FDA.
• Any information that was evaluated for the purpose of preparing the
submission of annual reports.
• Systems that ensure access to information for facilitating timely follow-up
and inspection by the FDA.

A keystone of the medical device reporting regulation is the ability for a

company to effectively determine when an event meets the criteria for MDR.
According to the guidance “Medical Device Reporting for Manufacturers,”
MDR reportable events are events that manufacturers become aware of that
reasonably suggest that one of their marketed devices may have caused or
contributed to a death or serious injury. This also applies to devices that have
malfunctioned in such a way that they would be likely to cause or contribute to
a death or injury if the malfunction were to recur.7

MDR issues noted in actual warning letters:

• Insufficient or no documented instructions for completing the procedures
for internal systems or completing required FDA forms.
• Incomplete procedural documentation, such as the omission of key terms
specified in the regulation, which could lead to an incorrect reportability
decision.
• Insufficient or no instructions for properly conducting investigations of
reportable events, evaluating the cause of events, and initiating a CAPA.

Most Common Reasons for FDA Form 483 Observations and Warning Letters in Medical Device 5
Environments

“MasterControl has helped
us be able to proactively
address concerns from the
FDA and be able to show
that we thought not one,
but two steps ahead in
every part of our process,
which helped us ultimately
gain approval.”
– Nina Tandon, CEO, Co-founder,
EpiBone9
Most Common Reasons for FDA Form 483 Observations and Warning Letters in Medical Device
Environments
Industry Brief
MasterControl eMDRTM (electronic medical device reporting) digitises and
streamlines device event reporting processes to ensure that reporting and
submission of MDR data is timely and consistent. It implements a structured
workflow to your MDR tasks and integrates with document control processes
to ensure all documents are complete, accurate, and error-free to help ensure
compliance.
Process Validation
21 CFR 820.75(a) states that where the results of a process cannot be fully
verified by subsequent inspection and testing, the process must be validated
with a high degree of assurance and approved according to established
procedures. The validation activities and results, including the date and
signature of the individual(s) approving the validation and, where appropriate,
the major equipment validated, must be documented.
Process validation is defined as the collection and evaluation of data, from
the process design stage through commercial production, which establishes
scientific evidence that a process is capable of consistently delivering quality
product. Process validation involves a series (stages) of activities that take
place over the life cycle of the product and processes.8
Validation issues noted in actual warning letters:
• Component materials used in sterilisation validation were not
representative of the facility’s routinely sterilised components in each
product family.
• There is no documented evidence that component materials the firm
sterilises were represented based on worst-case components by product
families in the most recent sterilisation validation summary report.
• Process validation procedure does not identify the frequency for validating
and revalidating manufacturing processes. The validation records do
not show that the processes have been evaluated with any uniformity
proportionate with the risk it poses to the finished device.
• Failure to adequately validate computer software used as part of
production for its intended use according to an established protocol.
MasterControl RiskTM gives you a complete view of your enterprise risk
landscape. This includes all product lines, business units, procedures, quality
management, document control, and more. The risk management software
tracking and analysis features let you easily identify and mitigate long-term
system, process, and product risks.
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 Industry Brief

About MasterControl
MasterControl Inc. is a leading provider of cloud-based quality, compliance
and production management software for life sciences and other regulated
industries. Our mission is the same as that of our customers – to bring life-changing
products to more people sooner. The MasterControl Platform helps organisations
digitise, automate and connect critical processes across the regulated product
development life cycle.
Learn more at mastercontrol.com.

References
1. “CFR – Code of Federal Regulations Title 21,” U.S. Food and Drug
Administration (FDA), Apr. 1, 2020.
2. “Reorganization of The Center for Devices and Radiological Health,” U.S. Food
and Drug Administration (FDA), July 7, 2020.
a. Supra Note2
3. “FDA 483 Observations and Warning Letter Trends,” Chalana Damron,
Crowell & Moring.
4. “Complaint Files,” Stanley Liu, consumer safety officer, Premarket Programs
Branch, CDRH, U.S. Food and Drug Administration (FDA).
5. “How a Platform Approach to Technology Modernization Is Transforming
Manufacturing Performance and Quality,” MasterControl Case Study.
6. “Overview of Quality System Regulations (QSR) for Medical Devices,” Beckie
Ellis, FDA Medical Device Industry Coalition.
7. “Medical Device Reporting for Manufacturers,” U.S. Food and Drug
Administration (FDA) Guidance for Industry and FDA Administration Staff,
Nov. 8, 2016,
8. “Process Validation: General Principles and Practices,” U.S. Food and Drug
Administration (FDA), Jan. 2011.
9. “Why EpiBone Chose MasterControl for Their Quality Management System,”
MasterControl video.

Most Common Reasons for FDA Form 483 Observations and Warning Letters in Medical Device 7
Environments