Conclusion
These days, it should never be a shock to a company that they received a Warning Letter, experts note. If the
FDA is not satisfied with the response you gave to the 483, or if the 483 raised serious issues that you ignored
or minimized, the Warning Letter is almost inevitable.
But the good news is that the FDA generally just wants to see proof that you understand the problems it raised
and are taking concrete steps to address them. Unless the Warning Letter is addressing serious and imminent
threats to public health, the FDA is likely to work with you to fix the situation rather than “punish” you and
harm your operation.
The FDA doesn’t show any sign of letting up on CAPA citations. Wise drug and device makers shouldn’t either.
Getting CAPA right will help avoid the most common observations and citations altogether.
Finally, the FDA’s approach puts a lot of responsibility on drug and device companies to develop a cohesive
response to a Warning Letter. It is up to you to give the FDA a good response plan that includes ways you will
keep the FDA in the loop as you make progress.
Additional Resources
To track Warning Letters for trends by topic, Center and company:
http://www.fda.gov/foi/warning.htm
How to Respond to an FDA
Warning Letter or 483 Observation
The odds of receiving an Inspectional Observation (483) or a subsequent Warning Letter are
sharply on the rise, and the seriousness of each remains high. The FDA, thanks to its renewed focus
on enforcement and revitalizing the agency, has issued far more 483s and Warning Letters, and
conducted increasingly more inspections since 2008.
According to FDA enforcement statistics, the number of Warning Letters in Fiscal Year 2008 was 445,
but that number rose to 1720 in FY 2011 (a shocking 286% increase). The number of product recalls
has climbed steadily from 5,778 in FY 2008, to a peak of 9,361 in FY 2010, and leveling off to 9,288 in
FY 2011.
It is also important to recognize that when the FDA does conduct an inspection, they’ve arguably
gotten tougher and more targeted in the past several years. Warning Letters for drug manufacturers
hit on many areas, but for device makers it is more obvious what FDA looks at: In 2010, Corrective
and Preventive Action (CAPA) accounted for the second and fourth most cited issues in FDA 483
observations. In 2011, CAPA-related citations were ranked first and third. In 2011, medical device
firms were issued 175 Warning Letters. Of those, 85% had CAPA citations, and 80% had purchase
control citations.
How to Find Investigator’s Inspection History:
Early trends in 2012 show that the FDA will continue issuing a steady stream of Warning Letters, and
that CAPA is likely to be a driving force behind them.
CBER
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
ComplianceActivities/ucm165743.htm
Trend: More Warning Letters, Recalls and Questions
CDER
http://www.fda.gov/Drugs/InformationOnDrugs/ucm135198.htm
CDRH
Submit request under Freedom of Information Act
Quality Management and Regulatory Compliance Solutions:
http://www.assurx.com/quality-compliance-software-solutions.htm
Many FDA regulated drug and device companies remain puzzled by the entire process.
What is a 483?
How is it different from an FDA Warning Letter?
If I receive a 483 will I then get a Warning Letter?
Should I respond differently to a 483 or a Warning Letter?
These are all questions that will be addressed by this AssurX White Paper.
To find out how AssurX can help with your compliance needs, please call 1-888-9-ASSURX.
What’s the Difference?
It’s key at the outset to understand the difference between a 483 and a Warning Letter.
Form 483s were created in 1953 and designed to eliminate the possibility of the FDA taking stronger action
(such as issuing a Warning Letter) without prior notice. In some ways, think of the 483 as the warning a traffic
cop might give you for having a broken tail light. The Warning Letter would be issued only if, when the traffic cop
next checked in on you and your car, he found you hadn’t fixed the light. If you had fixed the light, or had already
© Copyright 2012, AssurX, Inc. All rights reserved.
AssurX, Inc. • Tel 888.927.7879 • Fax 408.776.1267 • [email protected] • www.assurx.com
2012
presented a realistic plan with a timetable demonstrating that you would fix the light, and in fact check out all
the lights on your car, you probably wouldn’t get a Warning Letter.
The FDA views the 483 as a tool that provides immediate post-inspection feedback on what problems, if any, an
inspector actually saw at your facility. It also “establishes a background of prior warning,” FDA’s New England
District official Mark Lookabaugh told the MassMEDIC group.
After the Inspection
Patricia Holobaugh, FDA Center for Biologics Evaluation and Research Division of Inspections and Surveillance,
outlined what happens as an inspection ends.
After the Form 483 is presented and discussed the company may respond in a letter. Send the response letter to
the address on the 483 or ask the FDA investigator for the HQ Center address.
Next, the inspection report is written by the FDA investigator and sent to the Center. The Center evaluates the
report and determines the corrective action. “We write a letter following most inspections,” Holobaugh said.
Instruments 12, 16 and 382, which were in use during the manufacture of Lots 5, 6, and 7 of Product X
had exceeded due dates for their next scheduled calibrations.
The device company’s response also cites the appropriate FDA rule. In this case, it is 21 CFR 211.68(a).
The device company’s effective response then goes on to tell the FDA that the instruments were calibrated and
found to be within limits (records attached), usage in manufacture of Product X has no effect on quality, the
calibration program will be reviewed to assure there are no other instances like this observation, and review of
the program along with any needed corrections will be completed within sixty days. “Documentation will be
submitted,” the device company response states clearly.
That documentation is critical, current and former FDA inspectors regularly state, because the agency essentially
takes this view: If it wasn’t documented, it didn’t happen.
Why That 483 Response Probably Avoided a Warning Letter
According to Lookabaugh, there are four key reasons that kind of 483 response would be successful:
• Immediate corrections made when possible and adequately documented
Here’s how the FDA classifies the inspections:
• NAI: No Action Indicated
• Effect of deviation on product quality is objectively assessed
• VAI: Voluntary Action Indicated
• Systemic and/or global ramifications of observation are addressed
• OAI: Official Action Indicated
• Target date set for ongoing actions, with promise to submit documentation
Responding to a 483
Lookabaugh stresses that companies should make a written response to the 483 within 15 days, even if the initial
response is just preliminary. In that response, demonstrate that you understand the relative significance of the
Inspector’s observations as they relate to product quality. You should also acknowledge the observations and
describe the corrections you are undertaking to fix them. Make “immediate corrections if possible, otherwise set
[a] realistic time frame,” Lookabaugh advised.
Your response should also provide assurance, whenever possible, that the quality of the distributed product will
not have a negative impact on public health or safety. That response should also address all deficiencies and
provide a plan of action with target dates.
Remember our traffic cop and your warning for the busted tail light? “Always expect FDA follow-up,” he says. In
other words, they will come back to make sure you fixed the tail light.
Finally, make certain your 483 response emphasizes that “global” or “systemic” issues have been addressed.
Going back to our broken tail light example, this is a good time to tell the FDA that you have also inspected all of
your exterior lighting and it’s either fine or you fixed what was out. Don’t be too literal with the agency and just
address a narrow area where they raised a concern.
Example: A Strong 483 Response
Lookabaugh offered up the kind of 483 response that would likely satisfy the FDA and prevent the issuance of a
Warning Letter.
In his example, the device company notes in its response that the agency made the following Inspectional
Observation in the 483:
c o m p l i a n c e
2
Now, Warning Letters
But what if your response is judged inadequate or the FDA otherwise issues a Warning Letter? First off,
understand that the agency even at this point is strongly hoping you will voluntarily take the corrective action
required so they can settle this case and move on to something else. They are “intended to elicit voluntary
correction,” Lookabaugh said.
However, if you fail to address the issues raised in a Warning Letter, your company can face some serious
repercussions, including: recall, seizure, injunction, monetary fine, debarment, disqualification, license
suspension or revocation, and prosecution.
The issuance of a Warning Letter certainly raises the stakes after a 483. The violations it contains represent
concerns not only of an investigator, but of the District and/or Center compliance officers.
Responding to a Warning Letter
Your first action after you receive a Warning Letter should be to immediately notify top management of the
letter and give them an idea of the scope of the problem. You should also contact the FDA’s District Director of
Compliance Officer, Lookabaugh said. In your written response to them, you should acknowledge your obligation
to comply with the law, discuss the impact the issues raised will have on product quality, address any broader
or systemic corrections the Warning Letter may have raised, and offer your corrective actions and timetable for
completing them.
Ask to meet with the FDA, Lookabaugh advised. That meeting is important for a number of reasons, including:
• Ensuring there is common understanding of GMP concerns
• Verifying the adequacy of proposed corrections
3
w h i t e p a p e r
presented a realistic plan with a timetable demonstrating that you would fix the light, and in fact check out all
the lights on your car, you probably wouldn’t get a Warning Letter.
The FDA views the 483 as a tool that provides immediate post-inspection feedback on what problems, if any, an
inspector actually saw at your facility. It also “establishes a background of prior warning,” FDA’s New England
District official Mark Lookabaugh told the MassMEDIC group.
After the Inspection
Patricia Holobaugh, FDA Center for Biologics Evaluation and Research Division of Inspections and Surveillance,
outlined what happens as an inspection ends.
After the Form 483 is presented and discussed the company may respond in a letter. Send the response letter to
the address on the 483 or ask the FDA investigator for the HQ Center address.
Next, the inspection report is written by the FDA investigator and sent to the Center. The Center evaluates the
report and determines the corrective action. “We write a letter following most inspections,” Holobaugh said.
Instruments 12, 16 and 382, which were in use during the manufacture of Lots 5, 6, and 7 of Product X
had exceeded due dates for their next scheduled calibrations.
The device company’s response also cites the appropriate FDA rule. In this case, it is 21 CFR 211.68(a).
The device company’s effective response then goes on to tell the FDA that the instruments were calibrated and
found to be within limits (records attached), usage in manufacture of Product X has no effect on quality, the
calibration program will be reviewed to assure there are no other instances like this observation, and review of
the program along with any needed corrections will be completed within sixty days. “Documentation will be
submitted,” the device company response states clearly.
That documentation is critical, current and former FDA inspectors regularly state, because the agency essentially
takes this view: If it wasn’t documented, it didn’t happen.
Why That 483 Response Probably Avoided a Warning Letter
According to Lookabaugh, there are four key reasons that kind of 483 response would be successful:
• Immediate corrections made when possible and adequately documented
Here’s how the FDA classifies the inspections:
• NAI: No Action Indicated
• Effect of deviation on product quality is objectively assessed
• VAI: Voluntary Action Indicated
• Systemic and/or global ramifications of observation are addressed
• OAI: Official Action Indicated
• Target date set for ongoing actions, with promise to submit documentation
Responding to a 483
Lookabaugh stresses that companies should make a written response to the 483 within 15 days, even if the initial
response is just preliminary. In that response, demonstrate that you understand the relative significance of the
Inspector’s observations as they relate to product quality. You should also acknowledge the observations and
describe the corrections you are undertaking to fix them. Make “immediate corrections if possible, otherwise set
[a] realistic time frame,” Lookabaugh advised.
Your response should also provide assurance, whenever possible, that the quality of the distributed product will
not have a negative impact on public health or safety. That response should also address all deficiencies and
provide a plan of action with target dates.
Remember our traffic cop and your warning for the busted tail light? “Always expect FDA follow-up,” he says. In
other words, they will come back to make sure you fixed the tail light.
Finally, make certain your 483 response emphasizes that “global” or “systemic” issues have been addressed.
Going back to our broken tail light example, this is a good time to tell the FDA that you have also inspected all of
your exterior lighting and it’s either fine or you fixed what was out. Don’t be too literal with the agency and just
address a narrow area where they raised a concern.
Example: A Strong 483 Response
Lookabaugh offered up the kind of 483 response that would likely satisfy the FDA and prevent the issuance of a
Warning Letter.
In his example, the device company notes in its response that the agency made the following Inspectional
Observation in the 483:
c o m p l i a n c e
2
Now, Warning Letters
But what if your response is judged inadequate or the FDA otherwise issues a Warning Letter? First off,
understand that the agency even at this point is strongly hoping you will voluntarily take the corrective action
required so they can settle this case and move on to something else. They are “intended to elicit voluntary
correction,” Lookabaugh said.
However, if you fail to address the issues raised in a Warning Letter, your company can face some serious
repercussions, including: recall, seizure, injunction, monetary fine, debarment, disqualification, license
suspension or revocation, and prosecution.
The issuance of a Warning Letter certainly raises the stakes after a 483. The violations it contains represent
concerns not only of an investigator, but of the District and/or Center compliance officers.
Responding to a Warning Letter
Your first action after you receive a Warning Letter should be to immediately notify top management of the
letter and give them an idea of the scope of the problem. You should also contact the FDA’s District Director of
Compliance Officer, Lookabaugh said. In your written response to them, you should acknowledge your obligation
to comply with the law, discuss the impact the issues raised will have on product quality, address any broader
or systemic corrections the Warning Letter may have raised, and offer your corrective actions and timetable for
completing them.
Ask to meet with the FDA, Lookabaugh advised. That meeting is important for a number of reasons, including:
• Ensuring there is common understanding of GMP concerns
• Verifying the adequacy of proposed corrections
3
w h i t e p a p e r
• Revealing if further action is planned by the FDA
Resources: Sample FDA 483 Observation worksheet (Partial)
• Achieving agreement on how to proceed
• Providing a written summary, including any clarifications and additional commitments from either side
• Setting a timetable for periodic updates on progress
Your company can avoid “unnecessary problems” with the FDA as long as your response avoids the following:
unrealistic goals, blaming everything on a lack of training, trivializing the product complaints, failing to
proofread your correspondence, citing other firms’ practices as an excuse for your own, and failing to implement
promised corrections.
Attorney Peter Reichard with Shepard Mullin works closely with drug and device companies and former FDA
officials. He stressed that your Warning Letter response should focus on how you are addressing the problem.
“Companies have a tendency to try and explain something, but the FDA is not interested in that,” he says. “They
just want to know your plan and that you followed up,” he says.
Part of that plan, Reichard says, is to put together a Warning Letter response team that goes beyond regulatory
personnel. Include those involved in business and legal issues and those who keep a handle on resources and
expenditures, he advised.
Avoiding Warning Letters
FDA’s Lookabaugh perhaps summed it up better than anyone when he said “The only proven technique for
avoiding enforcement actions [is] establishing an effective Quality System.” And the FDA defines “establish” in
this instance as a Quality System that is defined, documented and implemented.
Companies that have SOPs and teams in place to handle process problems tend to do a better job of avoiding
Warning Letters, agreed Adam Bloom, an attorney in Reed Smith’s Life Sciences practice.
But the absolute “worst-case” scenario is to become a repeat offender in the eyes of the FDA, he said. “If you said
you would fix something, and they come back a year or two later and find the same problems,” they will view
your harshly, he added.
Example: Mammography Facilities
Mammography facilities are just one of several industries that are subject to a Warning Letter if found to be in
violation of laws administered by the FDA. A Warning Letter is considered a public record and is posted on the
FDA’s website for public viewing. Therefore, Warning Letters are one of the FDA’s principal means of achieving
prompt, voluntary compliance, offering recipients a chance to submit a plan of correction so that enforcement
measures can be avoided. A noncompliant mammography facility, for example, could expect to receive a
Warning Letter from one of the FDA’s field offices detailing the problems found during an inspection and steps
that it needs to take within 15 business days of receipt of the letter.
A facility that fails to respond to a Warning Letter or to correct problems promptly may be re-inspected by the
FDA at a cost to the facility. The facility also may be subject to an enforcement or administrative action that
could include a directed plan of correction, suspension or revocation of its certificate, civil money penalties, an
injunction, and other regulatory or administrative actions to ensure that it corrects the violation(s).
Fortunately, most facilities never find themselves in this situation. “Less than 50 percent of facilities have any
inspection findings and less than 5 percent of all facilities are issued a Warning Letter,” reports Mike Divine,
MQSA Compliance Expert with the FDA. “And of those, most never have compliance problems after that.”
FDA 483 Observation Partial Worksheet Example
c o m p l i a n c e
4
5
w h i t e p a p e r
• Revealing if further action is planned by the FDA
Resources: Sample FDA 483 Observation worksheet (Partial)
• Achieving agreement on how to proceed
• Providing a written summary, including any clarifications and additional commitments from either side
• Setting a timetable for periodic updates on progress
Your company can avoid “unnecessary problems” with the FDA as long as your response avoids the following:
unrealistic goals, blaming everything on a lack of training, trivializing the product complaints, failing to
proofread your correspondence, citing other firms’ practices as an excuse for your own, and failing to implement
promised corrections.
Attorney Peter Reichard with Shepard Mullin works closely with drug and device companies and former FDA
officials. He stressed that your Warning Letter response should focus on how you are addressing the problem.
“Companies have a tendency to try and explain something, but the FDA is not interested in that,” he says. “They
just want to know your plan and that you followed up,” he says.
Part of that plan, Reichard says, is to put together a Warning Letter response team that goes beyond regulatory
personnel. Include those involved in business and legal issues and those who keep a handle on resources and
expenditures, he advised.
Avoiding Warning Letters
FDA’s Lookabaugh perhaps summed it up better than anyone when he said “The only proven technique for
avoiding enforcement actions [is] establishing an effective Quality System.” And the FDA defines “establish” in
this instance as a Quality System that is defined, documented and implemented.
Companies that have SOPs and teams in place to handle process problems tend to do a better job of avoiding
Warning Letters, agreed Adam Bloom, an attorney in Reed Smith’s Life Sciences practice.
But the absolute “worst-case” scenario is to become a repeat offender in the eyes of the FDA, he said. “If you said
you would fix something, and they come back a year or two later and find the same problems,” they will view
your harshly, he added.
Example: Mammography Facilities
Mammography facilities are just one of several industries that are subject to a Warning Letter if found to be in
violation of laws administered by the FDA. A Warning Letter is considered a public record and is posted on the
FDA’s website for public viewing. Therefore, Warning Letters are one of the FDA’s principal means of achieving
prompt, voluntary compliance, offering recipients a chance to submit a plan of correction so that enforcement
measures can be avoided. A noncompliant mammography facility, for example, could expect to receive a
Warning Letter from one of the FDA’s field offices detailing the problems found during an inspection and steps
that it needs to take within 15 business days of receipt of the letter.
A facility that fails to respond to a Warning Letter or to correct problems promptly may be re-inspected by the
FDA at a cost to the facility. The facility also may be subject to an enforcement or administrative action that
could include a directed plan of correction, suspension or revocation of its certificate, civil money penalties, an
injunction, and other regulatory or administrative actions to ensure that it corrects the violation(s).
Fortunately, most facilities never find themselves in this situation. “Less than 50 percent of facilities have any
inspection findings and less than 5 percent of all facilities are issued a Warning Letter,” reports Mike Divine,
MQSA Compliance Expert with the FDA. “And of those, most never have compliance problems after that.”
FDA 483 Observation Partial Worksheet Example
c o m p l i a n c e
4
5
w h i t e p a p e r
Resources: Sample FDA Warning Letter
c o m p l i a n c e
Resources: Sample FDA Warning Letter Continued
FDA Warning Letter Page 1 of 3
FDA Warning Letter Page 2 of 3
6
7
w h i t e p a p e r
Resources: Sample FDA Warning Letter
c o m p l i a n c e
Resources: Sample FDA Warning Letter Continued
FDA Warning Letter Page 1 of 3
FDA Warning Letter Page 2 of 3
6
7
w h i t e p a p e r
Resources: Sample FDA Warning Letter Continued
FDA Warning Letter Page 3 of 3
c o m p l i a n c e
8
w h i t e p a p e r
Conclusion
These days, it should never be a shock to a company that they received a Warning Letter, experts note. If the
FDA is not satisfied with the response you gave to the 483, or if the 483 raised serious issues that you ignored
or minimized, the Warning Letter is almost inevitable.
But the good news is that the FDA generally just wants to see proof that you understand the problems it raised
and are taking concrete steps to address them. Unless the Warning Letter is addressing serious and imminent
threats to public health, the FDA is likely to work with you to fix the situation rather than “punish” you and
harm your operation.
The FDA doesn’t show any sign of letting up on CAPA citations. Wise drug and device makers shouldn’t either.
Getting CAPA right will help avoid the most common observations and citations altogether.
Finally, the FDA’s approach puts a lot of responsibility on drug and device companies to develop a cohesive
response to a Warning Letter. It is up to you to give the FDA a good response plan that includes ways you will
keep the FDA in the loop as you make progress.
Additional Resources
To track Warning Letters for trends by topic, Center and company:
http://www.fda.gov/foi/warning.htm
How to Respond to an FDA
Warning Letter or 483 Observation
The odds of receiving an Inspectional Observation (483) or a subsequent Warning Letter are
sharply on the rise, and the seriousness of each remains high. The FDA, thanks to its renewed focus
on enforcement and revitalizing the agency, has issued far more 483s and Warning Letters, and
conducted increasingly more inspections since 2008.
According to FDA enforcement statistics, the number of Warning Letters in Fiscal Year 2008 was 445,
but that number rose to 1720 in FY 2011 (a shocking 286% increase). The number of product recalls
has climbed steadily from 5,778 in FY 2008, to a peak of 9,361 in FY 2010, and leveling off to 9,288 in
FY 2011.
It is also important to recognize that when the FDA does conduct an inspection, they’ve arguably
gotten tougher and more targeted in the past several years. Warning Letters for drug manufacturers
hit on many areas, but for device makers it is more obvious what FDA looks at: In 2010, Corrective
and Preventive Action (CAPA) accounted for the second and fourth most cited issues in FDA 483
observations. In 2011, CAPA-related citations were ranked first and third. In 2011, medical device
firms were issued 175 Warning Letters. Of those, 85% had CAPA citations, and 80% had purchase
control citations.
How to Find Investigator’s Inspection History:
Early trends in 2012 show that the FDA will continue issuing a steady stream of Warning Letters, and
that CAPA is likely to be a driving force behind them.
CBER
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
ComplianceActivities/ucm165743.htm
Trend: More Warning Letters, Recalls and Questions
CDER
http://www.fda.gov/Drugs/InformationOnDrugs/ucm135198.htm
CDRH
Submit request under Freedom of Information Act
Quality Management and Regulatory Compliance Solutions:
http://www.assurx.com/quality-compliance-software-solutions.htm
Many FDA regulated drug and device companies remain puzzled by the entire process.
What is a 483?
How is it different from an FDA Warning Letter?
If I receive a 483 will I then get a Warning Letter?
Should I respond differently to a 483 or a Warning Letter?
These are all questions that will be addressed by this AssurX White Paper.
To find out how AssurX can help with your compliance needs, please call 1-888-9-ASSURX.
What’s the Difference?
It’s key at the outset to understand the difference between a 483 and a Warning Letter.
Form 483s were created in 1953 and designed to eliminate the possibility of the FDA taking stronger action
(such as issuing a Warning Letter) without prior notice. In some ways, think of the 483 as the warning a traffic
cop might give you for having a broken tail light. The Warning Letter would be issued only if, when the traffic cop
next checked in on you and your car, he found you hadn’t fixed the light. If you had fixed the light, or had already
© Copyright 2012, AssurX, Inc. All rights reserved.
AssurX, Inc. • Tel 888.927.7879 • Fax 408.776.1267 • [email protected] • www.assurx.com
2012