white paper

The Top Three Mistakes

to Avoid When Responding
to an FDA Form 483

By David Elder, Vice President Strategic

Compliance Services, Parexel
On Your Mark: You Have 15 Days to
Avert a Non-Compliance Crisis

For biopharmaceutical and medical device companies, While roughly half of FDA inspections result in 483s,
the cost of non-compliance with current good only a fraction of those lead to a Warning Letter or
manufacturing practice (cGMP) regulations can be other serious enforcement action. For example, in
devastating. In addition to compromising patient health fiscal year 2014 (10/1/13-9/30/14), the FDA issued a
and safety, unresolved cGMP problems can land foreign total of 1,617 Form-483s to medical device and drug
firms on the FDA’s import alert list, banning them from manufacturers (972 and 645, respectively) but sent out
shipping products to the US until corrective actions are just 208 Warning Letters (114 and 94, respectively).
implemented and verified. And product recalls create a There is not a perfect correlation between 483s and
vicious cycle of loss: Remediation costs skyrocket while Warning Letters as 1) Warning Letters may be issued
revenues, reputation and stock prices sink. Last year, without a corresponding 483, e.g. by policy, some
one foreign-based generic drug maker struggling with potentially violative conditions are not reported on the
regulatory sanctions at facilities in both the US and India 483 (see Investigations Operations Manual Section
reported a 94% drop in net profit year-over-year. 5.2.3.3; advertising and promotion Warning Letters are
In the US, the cGMP enforcement process involves a typically not associated with an inspection); 2) 483 totals
staged escalation that begins with the FDA’s Form on the FDA’s website may not include some reports
FDA-483. The 483 is a set of observations regulators prepared outside the FDA’s automated system; and 3)
compile after inspecting a manufacturing facility and, 483s may be issued in a different fiscal year than the
importantly, before sending a Warning Letter. Warning related Warning Letter. But even with those caveats, the
Letters, while not considered formal agency action data show that a complete and timely 483 Response
per se (Regulatory Procedures Manual, Section 4.1.1) offers a real chance to avert trouble.
constitute a notice of violations that the agency expects However, there’s a catch: Your company only has 15 days
to be corrected. They lay the groundwork for other to prepare a 483 Response. The FDA will consider your
enforcement actions. The FDA posts all Warning analyses, corrective actions, and explanations when
Letters online. deciding whether or not to initiate compliance actions,
The 483 (“Notice of Inspectional Observations”) lists but only if you hit that deadline. Submitting a sloppy,
observed conditions or practices that in the opinion incomplete or otherwise inadequate response could
of the FDA investigators may constitute violations of make matters worse. And although responding to a
law. However, the 483 observations are not a final 483 is not mandatory, the vast majority of companies
determination of noncompliance. There may be do respond. This makes non-responders appear
extensive further review before the agency takes action. uncooperative, from which regulators likely may draw
Companies have opportunities (both oral and written) a negative inference.
during and after the inspection to make their views
known, to offer plans to remedy 483 observations, or
even to dispute observations they believe inaccurate
or not representing violations of law or regulation.

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Here are three of the most serious mistakes companies make and how you
can avoid them:

1
Tunnel Vision

Yes, the 483 included an observation that batch test encompass your procedures, policies and personnel
results were improperly deleted from the computer qualifications to explain why the issue wasn’t detected
at Station 5 on April 22 and FDA investigators found (or was detected but not remediated) through internal
a record of that deletion in the trash bin, not the auditing or via management oversight.
automatically generated audit trail. But your response The requirement for this degree of diligence in 483
should go well beyond the unfortunate trash bin incident responses is made explicit in FDA Warning Letters,
to analyze how it was possible for those deletions to which are posted online, exposing the alleged
occur in the first place. Was it a systemic failure or a manufacturing problems of your company to public
fluke? Was it a single rogue employee, an inadvertent scrutiny (another excellent reason to try and avoid
keystroke or a system-wide computer software them). The Letters often outline how and why 483
deficiency that allowed the audit trail function to be Responses fall short. In cGMP Warning Letters issued
disabled? And what about the product on the market to biopharmaceutical and medical device companies,
that relied on those test results? Is it impacted and, if one phrase pops up repeatedly: “You failed to identify
it is, how should that be addressed? the root cause.” Conducting an accurate and actionable
Your company needs to avoid offering corrections or root cause analysis requires an open mind, holistic
corrective actions that address a single incident. The goal thinking and deep expertise. And once the root cause
of your response should be to propose comprehensive, is discovered, it’s not sufficient to describe it in one
systemic actions that demonstrate your company’s sentence. A 483 Response should include a detailed
resolve to get at the root cause of the problem to prevent description of the root cause analysis, along with data
anything like that from ever happening again. In the substantiating the findings.
above example, remedies should both prevent further For example, in 2011 the Center for Drug Evaluation
noncompliant deletions at Station 5, but also ensure the and Research (CDER) cited one firm’s explanation of a
audit trail function works across your entire computer product contamination incident as inadequate. In a 483,
system so that no lab technician in any facility can either FDA investigators observed that: 1) 13 batches of the
intentionally or accidentally delete data without an company’s active pharmaceutical ingredient (API)
electronic record of the event. Your analysis should contained “black particles”; and 2) hydraulic oil was

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leaking in the manufacturing area. In response, the Figure 1:
company stated that it had repaired the leaking Narrow 483 Responses don’t work
equipment and that each time new leaking oil was
detected it would revise its procedure for process Language Used to Describe Source
deviation investigations “to address documentation of Inadequacy of 483 Response
the investigations, root cause analyses and corrective “Your response… only addresses Warning Letter
and preventive actions.” the five entries specifically July 2014
Not good enough. According to CDER, the firm’s discussed on the Form-483 (CDER)
response was “inadequate” because it “assumed that issued… your response does not
the black particles are hydraulic oil contamination, discuss any investigation into the
without an investigation or any identification of the missing records or address the
contaminant. Furthermore, you did not describe what root cause or extent of these
steps you will be taking with regard to the API deficient practices throughout your
manufactured using defective production equipment.” facility.”

Although the company took care of the leaking oil, it “Your response is inadequate in Warning Letter
failed to prove that the black particles were, indeed, that your investigation was May 2014
connected to the leaking oil. CDER wanted a deeper primarily limited to the discarded (CDER)
analysis, broader corrective measures and a full CGMP records cited in the Form
accounting of the final disposition of the defective FDA-483… The investigation did not
13 lots. include a comprehensive review of
all records in the waste area or a
thorough review of your firm’s
practice of destroying cGMP
records…”
“Your firm’s response did not Warning Letter
address why these activities were July 2014
not documented. In addition, your (CDRH)
firm did not consider a systemic
corrective action to include a
retrospective review of other
CAPAs to ensure that these reports
were adequately documented.”

KEY: CDER = FDA’s Center for Drug Evaluation and

Research; CDRH = FDA’s Center for Devices and
Radiological Health

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 2
Lack of Proof

One of the most common errors companies make in Figure 2:

responding to 483s is failing to provide documentation, Where’s the proof?
i.e. evidence of corrective action. For example, if a
company has revised its Standard Operating Procedures Language Used to Describe Source
(SOPs) and retrained employees, the 483 Response Inadequacy of 483 Response
should include the new SOP document and concrete We acknowledge your response Warning Letter
proof of the retraining sessions (e.g., times, dates, and that you have performed smoke March 2015
attendance records for the sessions.) It’s that simple. studies... However, your response… (CDER)
failed to provide a video of the new
smoke studies you indicated that
you performed.
We reviewed your firm’s response Warning Letter
and conclude that it is not March 2015
adequate. Your firm revised its (CDRH)
CAPA procedure. However… your
firm did not provide training
records on the revised procedure.
We acknowledge the revisions Warning Letter
made to SOP No. SGL-IMS-04 October 2014
(section 2.3), “Control of Records,” (CDER)
however, your firm provided no
evidence demonstrating that all
operators have been trained on
the revised procedure. Provide
documentation…

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 3
Risky
Remediation
Management

Time lines proposed for corrective action in a 483 ask for an extension, but be sure the request is justified
Response must be finely calibrated to the problem at and the new deadline can be met without further delay.
hand. Too often companies propose deadlines that are For example, pharmaceutical manufacturers procure
either unrealistically short or, at the other end of the materials and services to make their products. As a
spectrum, needlessly put off so that they’re robbed of result, they must continually monitor their suppliers
their urgency. It’s best to commit to goals, time lines through testing, oversight and audits of suppliers’
and milestones that are aggressive but achievable. If facilities in order to ensure that their specifications
extensions are needed, ask for them: If a problem can for the quality of materials and services are met. If the
be fixed on an acute basis, fix it. 483 cites cGMP problems with the qualification and
Let’s start with the 483 Response deadline itself. The monitoring of suppliers, corrective actions often are
FDA gives companies 15 days to craft a comprehensive extensive. For projects of this magnitude, only commit
response and propose a plan to correct all the to what you are sure you can deliver and establish
deficiencies listed in the 483. Yet it’s highly improbable interim controls to provide assurance of quality and
that complete investigations and implementation of conformance until permanent corrective actions can be
corrective actions can be completed within that time. implemented. Missed deadlines, lack of management
Some cGMP violations may be amenable to a thorough and/or staging for longer-term projects and poor
analysis and swift repair in less than two weeks and performance can destroy your company’s credibility
some may not. If all that is needed for compliance is a (as in the sample Warning Letters in Figure 3).
revised procedure and additional employee training, that
can often be accomplished in days, not weeks. (But don’t Your Last, Best Chance to Avoid Escalation of
forget to document the process and include your Regulatory Sanctions
evidence!) An effective 483 Response represents your company’s
When corrective actions take longer, the response cooperativeness and concomitant commitment to quality
submitted within 15 days must present clear, and patient safety. It is potentially your last, best chance
comprehensive corrective action plans with milestones, to avoid a Warning Letter after an inspection. A Warning
time lines and accountability for completion. For such Letter can delay product launches, harm your reputation
fixes that need longer time frames, a risk assessment and incur hefty damage control costs. If you can avoid the
may indicate the need to propose and implement an three most significant mistakes in your 483 Response,
interim controls plan with appropriate assurance of and take corrective action in a comprehensive and timely
quality, review, and accountability. If you later realize a manner, you will be on your way to achieving compliance
milestone can’t be met despite your firm’s best efforts, and restoring your company’s credibility with the FDA.

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 Responding to EU GMP Inspection Reports
Figure 3: Although procedures for handling inspections and
Don’t forget the interim controls! compliance in the EU differ slightly from the US,
the same criteria for an exhaustive, compelling
Language Used to Describe Source and acceptable response to observed GMP
Inadequacy of 483 Response problems apply.
In the EU, the competent authorities (CA) of the
Your response indicates that the Warning Letter
member states – analogous to the US FDA –
laboratory will stop using July 2012
perform Good Manufacturing Practice (GMP)
notebooks and replace them with (CDER) inspections for drug manufacturing facilities
analytical test forms and that a (devices are generally handled by Notified Bodies
project team will prioritize the new and are not discussed here). Although the
analytical forms and plan for full European Medicines Agency (EMA) can request
implementation by the end of 2012. inspections, one (or in some cases, several) of the
Your response is inadequate CAs will conduct the actual investigation and
because it does not include an record observations. Foreign inspections may
involve teams consisting of inspectors from more
interim plan to ensure adequate
than one CA. Inspectors will present their findings
documentation in the notebooks at the end of the inspection orally, and company
prior to the implementation of the officials can present a tentative remedial action
new forms. plan at that time, based on the feedback received
from the inspectors during the inspection.
“Your response indicates that Warning Letter
dynamic smoke studies for the (b) February 2012 The GMP Inspection Report is the final outcome of
(4) filling area would be completed (CDER) EU inspections and inspectors typically send the
contents of the initial report to companies for
by the end of November, 2011.
comment, along with a tentative date for the
However, your response is
issuance of the final document. Given that the
inadequate because you failed to findings already have been presented orally, the
include a detailed interim plan…” company should be in a position to provide a
Your responses, dated March 7, Warning Letter comprehensive remediation plan when they
receive the draft inspection report for comment.
2012 and May 29, 2012 were June 2012
Although there are no defined timelines,
inadequate. Your promised (CDRH)
inspectors typically expect a response within a
corrective actions referencing the two-week timeframe. In general, the timelines
updating of your complaint are quite similar to the FDA’s 15 working days. If
handling procedures have not yet applicable, inspectors will issue a GMP certificate
been implemented. within 90 days, according to statute.
The worst-case scenario for a company is when
the CA refuses to issue a GMP certificate or
revokes an existing one. Without the GMP
certificate, the drug product cannot be put on
the market in the EU. Although EU agencies do
not publish their inspection reports, they enter
the outcome of the inspection in a database with
limited public access (EudraGMDP). In principle,
although it is possible to obtain heavily redacted
inspection reports from EU CAs under freedom
of information laws, this is extremely time
consuming and is a course very rarely pursued.
In case of serious deficiencies posing possible
safety risks for patients, inspectors may take
immediate action.
Siegfried Schmitt, Ph.D., PAREXEL Consulting

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