It’s
generally nerve-wracking when the US Food and Drug Administration (FDA) shows
up at your door for an inspection. Even if you’re confident that everything is
in good shape around every corner.
To ensure
compliance with regulations, the FDA conducts inspections of all registered
establishments.
Once the inspection is closed out, it is categorized in one of
three ways based on the objectionable conditions noted (if any):
NAI - No
Action Indicated
VAI -
Voluntary Action Indicated
OAI -
Official Action Indicated
NAI and VAI
indicate that only minor objections were noted, whereas OAI indicates that
significant objectionable conditions that warrant FDA sanctions were cited. So
it’s the OAI inspections that make the headlines, and that no one wants to
experience first-hand.
FDA
inspection database link provided: http://www.fda.gov/ICECI/Inspections/ucm222557.htm
FDA inspection
data base search based on classification link provided: http://www.accessdata.fda.gov/scripts/inspsearch/index.cfm
Inspection
classifications listed in this report reflect the compliance status when the
report was generated and may not represent the final Agency determination. FDA
is disclosing the final inspection classification for inspections related to
currently marketed FDA-regulated products. The disclosure of this information
is not intended to interfere with planned enforcement actions, therefore some
information may be withheld from posting until such action is taken.
An OAI inspection classification occurs
when significant objectionable conditions or practices were found and
regulatory action is warranted to address the establishment's lack of
compliance with statute(s) or regulation(s).
A VAI inspection classification occurs
when objectionable conditions or practices were found that do not meet the
threshold of regulatory significance. Inspections classified with VAI
violations are typically more technical violations of the FDCA (Federal Food,
Drug, and Cosmetic Act (FD&C Act)
An NAI inspection classification occurs
when no objectionable conditions or practices were found during the inspection
or the significance of the documented objectionable conditions found does not
justify further actions.
If no
enforcement action is contemplated, or after enforcement action is
concluded,FDA provides inspected establishments with a final inspection report,
called an Establishment Inspection Report (EIR), which includes:
Brief
history of prior inspectional findings, including any action taken by FDA or
corrective action taken by the firm in response to a previous inspection
• The
investigator’s narrative report
• Any
refusals, voluntary corrections, or promises made by the firm’s management
• Copies of
forms the FDA issued to the firm during the inspection, including the FDA Form
483
FDA
proactively posts inspection reports (FDA Form 483s and EIRs) in the ORA
Electronic Reading Room when a high level of public interest is anticipated.
Also, FDA may post in the ORA Electronic Reading Room “frequently requested”
inspection reports as defined by the Electronic Freedom of Information Act
Amendments of 1996. FDA redacts non-public information, such as trade secrets,
from the inspection report before posting it.
Information
resources:
OSI :
http://www.fda.gov/cder/offices/dsi
List of
Disqualified or Restricted Investigators:
http://www.fda.gov/ora/compliance_ref/bimo/dis_res_assur.htm
OSI Warning
Letters Archive: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm247881.htm
NIDPOE
Letters: http://www.fda.gov/foi/nidpoe/default.html
Debarment List:
http://www.fda.gov/ora/compliance_ref/debar/default.htm
FDA inspection closeout:
At an
inspectional closeout, the FDA classifies the inspection outcome in three
different categories: NAI, VAI, and OAI.
NAI: No action indicated. Applicable for
two years and no FDA-483 issued.
VAI: Voluntary action indicated. Company
receives an FDA-483, but FDA will not pursue any regulatory actions like issue
of warning letter, injunction, or seizure. A routine inspection should not
occur within a two-year period.
OAI: Official action indicated. The firm
receives an FDA-483 where an investigator notes significant cGMP or quality
system regulation deficiencies. The establishment inspection report is written,
and regulatory actions are recommended to the compliance branch. Once the
investigation branch approves the recommendation to issue a warning letter, the
compliance branch issues the warning letter to the firm.
FDA warning letter:
For domestic
inspections, the district compliance branch issues the warning letter after an
FDA inspection. For foreign firms, the Center for Drugs and Radiological Health
(CDRH) issues the warning letter with or without automatic detention (import
alert). Once the warning letter is issued, the FDA expects a timely response
and adequate corrective actions. Typically, FDA schedules a re-inspection to
check the status of the corrective actions within a period of 6 to 12 months.
If a foreign
firm receives automatic detention/import alert after an inspection, the
products would be stopped at the U.S. border by the Customs and Border
Protection and the FDA as an immediate response to GMP quality system
regulation violations.
Form 483 and
Warning Letter’s are two serious documents issued by USFDA which are very
different in regulatory and legal prospective. “FDA 483 lists observations made
by the FDA representative during the inspection of a facility. They are
inspectional observations, and do not represent a final Agency determination
regarding firms compliance.” The FDA-483 can be amended after an inspection by
the investigator who issued it and re-issued.
The Warning Letter is a document that usually
originates from the FDA-483 observations that have been linked to citations by
one or more legal reviews within the Compliance and legal branch of the FDA. A
Warning Letter is informal and advisory. It communicates the agency's position
on a matter, but it does not commit FDA to taking enforcement action. For these
reasons, FDA does not consider Warning Letters to be final agency action on
which it can be sued. The Warning Letter is issued by the agency and not the
investigator.
Find below
mention brief information
FDA 482 –
Notice of Inspection
FDA 483 –
Notice of Inspectional observations
FDA 484 –
Receipt of samples
FDA 463 –
Affidavits
EIR –
Establishment Inspection Report
Inspection Basis of FDA
Compliance -
Inspection is conducted to investigate potential violations that have not
already resulted in an official agency action. These may include complaints
(trade or consumer) which are not the primary reason for the inspection
(otherwise see Consumer Complaint), recalls not classified as Class I, MedWatch
Reports, Adverse Drug Experience Reports, information from confidential
informants, etc.
Consumer
Complaint - Inspection is conducted in direct follow-up to a consumer
complaint. When a consumer complaint is received and the follow-up action
chosen is to conduct an inspection to confirm allegations within the complaint
or root causes that may have led to the condition described in the complaint,
this value should be selected.
F/U to Class
I Recall - Inspection is conducted in response to a Class I Recall conducted by
the establishment. The inspection is conducted to determine the root cause and
corrective actions addressing the violation(s) associated with the product.
F/U to Class
I Recall and F/U to Injunction - Inspection is conducted in response to a Class
I Recall conducted by the establishment AND pursuant to Permanent Injunction
and in accordance with the Consent Decree. In this instance, a firm under
permanent injunction has conducted a Class I Recall and the inspection is
conducted to determine the root cause and corrective actions addressing the
violation(s) associated with the product. Additionally, the inspection covers
the requirements of the Consent Decree for the Injunction. .
F/U to Class
I Recall and F/U to Warning Letter - Inspection is conducted in response to a
Class I Recall conducted by the establishment AND to f/u issues cited in a
Warning Letter issued to the establishment. In this instance, a firm that has
received a Warning Letter has conducted a Class I Recall and the inspection is
conducted to determine the root cause and corrective actions addressing the
violation(s) associated with the product in addition to covering corrective
actions responsive to the violations cited in the Warning Letter. The Warning
Letter may have issued as a result of the previous inspection or other
circumstance.
F/U to Class
I Recall and OAI Inspection F/U - Inspection is conducted in response to a
Class I Recall conducted by the establishment AND f/u to previous
OAI-classified inspection, where a regulatory or administrative action has not
been completed. This value captures the situation where the previous inspection
of the firm was classified OAI, but no official action was taken and the firm
has conducted a Class I Recall. The inspection is focused on the root causes of
the violations leading to the recall and may also address previously cited
violations. Before conducting an inspection of a firm where the previous
inspection was classified OAI with no regulatory action taken, be sure to
discuss what areas to cover with your supervisor and/or compliance officer.
F/U to
Injunction - Inspection is conducted pursuant to Permanent Injunction and in
accordance with the Consent Decree.
F/U to
Warning Letter - Inspection is conducted to follow-up issues cited in a Warning
Letter issued to the establishment.
OAI
Inspection F/U - Inspection is conducted to follow-up previous OAI-classified
inspection where a regulatory or administrative action has not been completed.
There can be a number of situations where an action is not taken although the
observations cited during the previous inspection met the threshold for an OAI
classification. Consult your supervisor and/or compliance officer prior to
initiating these types of inspections.
Surveillance
- Inspection is conducted as a routine assignment with no other indicators of
non-compliance. For example, an inspection of a firm whose previous inspection
was classified NAI; there have not been any complaints or recalls, etc.
Comprehensive
Reports (Include all applicable sections)
Reference: http://www.fda.gov/ICECI/Inspections/IOM/ucm122529.htm
A
comprehensive EIR should be prepared for initial inspections in all program
areas. It is essential to describe the products manufactured, the process the
manufacturing and storage environment, distribution patterns/interstate
commerce, individual responsibility of key employees, history of business, all
objectionable conditions observed, etc. All things pertinent to the operations
and management of the establishment should be included in these reports. The
comprehensive report may also be used for other situations requiring full
reporting such as Routine Surveillance - OAI. An abbreviated inspection does
not necessarily equate to an abbreviated report.
Required elements
Summary
Administrative data
History
Interstate (I.S.) Commerce
Jurisdiction (Products Manufactured
and/or Distributed)
Firm’s Training Program
Manufacturing/Design Operations
Manufacturing Codes
Complaints
Recall Procedures
Objectionable Conditions and
Management’s Response
Supporting Evidence and Relevance
Discussion with Management
Refusals
General Discussion with Management
Additional Information
Samples Collected
Voluntary Corrections
Exhibits Collected
Attachments
Routine Surveillance - NAI Reports
When FDA has an inspectional history
for the firm and no deficiencies were observed by the investigator, a brief
report may be prepared. The intent of this report is to include only the
required information about the firm and what areas were covered during the
inspection. “Change reporting” means information that differs from the previous
inspection report such as changes in management, products produced,
manufacturing processes, etc. Where these changes have occurred, the applicable
section heading in the EIR should be included. The elements may also be
captured in a “Summary of Findings Only” report without header information See
IOM 5.10.4.1.
Required elements
Summary
Administrative data
Refusals
General Discussion with Management
Samples Collected
Voluntary Corrections
Exhibits Collected
Attachments
Change reporting only:
History
Jurisdiction (Products Manufactured
and/or Distributed)
Individual Responsibility and Persons
Interviewed
Firm’s Training Program
Manufacturing/Design Operations
Manufacturing Codes
Routine Surveillance - VAI Reports
For firms with an inspectional
history and the outcome of the inspection is a VAI classification, the below
elements would be required, plus change reporting. Note that the difference in
the NAI versus the VAI report is the inclusion of narrative addressing
objectionable conditions observed during the inspection. Each objectionable
condition or practice must be documented in the EIR along with discussion of
the evidence, relevance and discussion with management.
Required elements
Summary
Administrative data
Objectionable Conditions and
Management’s Response
Supporting Evidence and Relevance
Discussion with Management
Refusals
Samples Collected
Voluntary Corrections
Exhibits Collected
Attachments
Change reporting only
History
Individual Responsibility and Persons
Interview
Firm’s Training Program
Manufacturing/Design Operations
Manufacturing Codes
Routine Surveillance - OAI
For an OAI surveillance inspection,
follow the guidance under Comprehensive Reports.
OAI Follow-up Inspection Reports
OAI follow-up inspections are
inspections conducted following an OAI classified inspection. Inspections of
this nature are conducted to determine whether corrective actions have been
implemented or significant violations continue. The outcome of these
inspections may range from NAI to OAI. The intended use of the EIR should be
the driving force of the content of these EIRs. Typically, the follow-up should
be done relatively soon after the previous inspection, so changes to products,
process, personnel, etc. should be minimal. The NAI and VAI reports should
focus on corrective actions implemented by firm management to correct the
violative conditions observed during the previous OAI inspection. Those reports
may be Summary of Findings only or may follow the other NAI and VAI report
formats above. An OAI follow-up inspection may lead to a regulatory action such
as seizure, injunction and/or prosecution. Those reports should focus on
documenting the continuing violations, responsibility for those violations, any
corrective actions implemented or inadequate corrective actions and defining
the new scope of violations observed including the products affected. Scope
should include additional lots, products, timeframe and distribution. These
reports should document all elements of JIVR (Jurisdiction, Interstate
Commerce, Violation and Responsibility). This allows for the report to support
whatever regulatory action is deemed necessary.
Required elements
Summary
Administrative data
Individual Responsibility and Persons
Interviewed
Objectionable Conditions and
Management’s Response
Supporting Evidence and Relevance
Discussion with Management
Refusals
Samples Collected
Voluntary Corrections
Exhibits Collected
Attachments
Change Reporting Only:
Interstate (I.S.) Commerce
Jurisdiction (Products Manufactured
and/or Distributed)
Manufacturing/Design Operations
Manufacturing Codes
Complaints
Inspection Reference, Guides &
Field Activities link: http://www.fda.gov/ICECI/Inspections/default.htm
Preventing an FDA warning letter
To prevent
an FDA warning letter, both pharmaceutical and device firms have to ensure that
there is a compliant quality system in place, and gain comprehensive knowledge
about CFR 211 and CFR 820 that govern the quality and safety requirements
pertinent to drugs and devices respectively. Following are some of the critical
steps that companies need to implement for avoiding an FDA warning letter.
Compliant quality system: A sound compliant quality system
must be established. A quality manual – with exhaustive documents on operating
procedures, work instructions, and testing specification, including in-process
and final acceptance testing of the medical device, and the finished
pharmaceutical product – must be maintained.
Quality department: The quality department must possess
adequate resources and personnel to adhere to the standards of the Quality
Management System (QMS). It must have the latitude to make appropriate changes
to the quality system as required, and must report directly to the executive
management or the CEO, so as to have the desired independence in its decision
making.
Internal/External Quality Audits: Trained individuals must conduct the
internal audits as per established procedures at appropriate intervals. The
audit schedules must include a detailed plan of what should be audited, how,
and when. For external audits, a capable external auditor/auditing body must be
identified. The findings from internal/external audits must be properly linked
to the CAPA system to ensure that the pain points and concerns identified
during audits are addressed effectively.
Robust CAPA system: While preventive actions enable
companies to avoid potential difficult situations, suitable corrective actions
help avoid warning letters and other enforcement actions and also help them
build a healthy relationship with the FDA. The effectiveness of CAPA must be
verified, and proof of action maintained, through proper documentation.
Training program: Effective training metrics aligned with established
procedures are necessary to ensure the availability of quality experts within
the firm. Result-oriented training programs require systematic planning,
execution, and evaluation.
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