Facing FDA Inspections

This presentation is compiled by “ Drug Regulations” a
non profit organization which provides free online
resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest
information from the world of Pharmaceuticals.

1/6/2014

1

This presentation is compiled from freely
available resources like the websites of FDA
and other free websites.
 “Drug Regulations” is a non profit
organization which provides free online
 Visit http://www.drugregulations.org for
latest information from the world of
Pharmaceuticals.


Drug Regulations : Online
Resource for Latest Information

1/6/2014

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◦ FDA inspections are stressful and worrisome.

◦ Failed FDA inspection costs include sales revenue
loss, stock price decline, and public embarrassment
from

FDA

warning

letters

and

FDA-483

observations.
◦ It is good to recalibrate by looking at frequently
asked questions when it comes to FDA inspections.


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◦ Yes.
◦ The FDA is not blind to reality.
◦ FDA’s charter is to protect public safety.
◦ If people, through product liability litigation, are having
to take matters into their own hands to go after

companies for putting ineffective or unsafe products on
the market, FDA could be seen as not performing its
task.
◦ So yes, FDA pays very close attention to product liability
litigation.

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

Prior to an inspection, the investigator(s) will create an inspection
plan that is largely based on the following information:
◦ Any previous establishment inspection reports (EIRs)
◦ Any previous FDA Form 483 observations, especially those that require
follow-up
◦ Company responses (to FDA-483s) and commitments

◦ Firm’s website (including product literature, executive profiles, physical
location profiles, recent press releases, etc.)
◦ Consumer complaints that have come in since the last inspection
◦ Adverse events that have come in since the last inspection
◦ Any recalls or other field activities that have occurred since the last
inspection


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◦ Any product submissions and applications, specifically to find critical
components or ingredients or processes that were of concern to FDA

reviewers
◦ Online web research can be further broken into three main areas:
 Online videos of your products in use (including if consumers have posted
videos comparing/contrasting to other competing products, etc.)
 Social media sites (especially for complaints about your product)

 Searches for your company name or product name(s) along with key words
(such as “review” or “fraud” or “FDA”).


An effective, independent FDA compliance gap analysis can help
you pinpoint areas to strengthen in your compliance efforts

before the FDA investigator arrives.

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◦ Yes.

◦ FDA investigators treat a closeout or follow-up
inspection as a normal inspection.
◦ You can be cited for new or additional items.


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

PAI inspections are Level 2 QSIT inspections by default.



FDA reviewers of a submission will identify areas of concern for
the investigator to look at during the inspection (such as GCP
data integrity controls).



PAI inspections may cover everything from
◦ Nonclinical supporting GLP-compliance,
◦ GCP compliance,
◦ GMP compliance,
◦ Even delve into how the company will monitor and control the product
once it is approved and on the market.


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

A level 2 QSIT inspection is a comprehensive

inspection, covering all four major quality
system subsystems
◦ Management controls,
◦ Development,
◦ CAPA, and

◦ Production and process controls

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

It will also involve the remaining three subsystems
◦ Facilities
◦ Equipment controls,
◦ Materials and supplier controls, and records controls



These

three

subsystems

cut

across

all

four

major

subsystems.


Thus, 21 CFR 11 controls will be reviewed and inspected
throughout the PAI, not just during review of the design

and development (e.g., design control) subsystem.

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

FDASIA 2012 expressly granted FDA the power to require
supplier audit reports during regular inspections (see Title
VII of FDASIA).



FDA discourages investigators from asking for the report
in the hopes that this will encourage firms to be more
candid and clear in supplier audits.



Unfortunately, as was painfully shown during the recent
Heparin scandal, FDA’s hope has not panned out.


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

Far too many firms conduct “meet and greet”

supplier audits with little meaningful impact.


FDA investigators are now taking advantage
of FDASIA’s new powers and requesting
copies of supplier audit reports.


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

FDA has always requested supplier audit

reports
◦ FDA Compliance Policy Guide, section 130.300,
◦ FDA

Access

to

Results

of

Quality

Assurance

Program Audits and Inspections
◦ During directed or “for cause” inspections of a

sponsor or monitor of a clinical trial

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◦ In inspections where access to such records is

authorized by statute (such as FDASIA)
◦ When public safety is at risk
◦ In litigation (or in support thereof)
◦ When executing a search warrant
◦ When a firm’s internal audit program is insufficient
or otherwise deemed ineffective by FDA.

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

This last point is often overlooked.



Technically, if the FDA investigator writes down a Form FDA-483
observation that a firm’s quality audit program is insufficient, the FDA
investigator can then review the firm’s supplier audit reports.



It is thus in a firm’s interest to ensure that it has a robust, FDA supplier
audit program that can withstand both FDA investigator and product
liability litigator scrutiny.



Finally, always remember that FDA counts any corrective actions from
supplier audits as CAPA documentation and freely open to review by any
FDA investigator.


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

As of the end of 2013, FDA’s special enforcement of 21
CFR 11 (e.g., "Part 11") is still ongoing.



Part 11 will come up throughout an inspection



It is a regulation that cuts across all quality system
subsystems.



If records are used or kept in digital form, or if a
computerized system is used to automate a regulated
process (such as production, lab testing, etc.), then the
FDA investigator will ask Part 11-relevant questions.

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

FDA looks to see if you are verifying the functions that you use of a software or a
computerized system in your environment, especially those functions related to

data integrity.


For instance, with a spreadsheet macro, the FDA investigator will expect to see a
simple verification of your use of the macro in your environment, documented
with a validation protocol, document testing, and a summary report.



Do not validate Excel, just the use of the macro within your environment.
Questions that the FDA investigator might ask include:
◦

How do you know the results of the macro are correct?

◦

Are complete?

◦

Did not drop off various data inputs? and so forth.

◦

These types of Part 11 validation are the ones to concentrate on.


1/6/2014

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

FDA

treats

all

photographs, videos, documents, notes, etc.
as confidential.


All such items go through FOIA to redact
such sensitive information before they are
released.


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

Consider making sure to identify in your inspection notes what
photographs the FDA investigator took



If possible, take a similar photograph.



In your response to the inspection,
◦ make sure to identify the photograph and

◦ any specific confidential or trade secret information that may have
inadvertently been captured by the FDA photograph.


This will help FDA to redact the appropriate information



Provide you some degree of assurance that they understand and
acknowledge the situation.

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

FDASIA 2012 granted FDA the power to conduct

remote and even online/virtual inspections.


FDA is currently not positioned to take advantage of
this.



The agency is planning to start a pilot program
wherein part of the inspection will be conducted
remotely (e.g., remote document review) followed by

a briefer onsite inspection portion.

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

Keep in mind that at its core, FDA is a regulatory enforcement
agency.



As such, during inspections, it is technically collecting evidence.



For companies doing all the right things, it is in their interest to
have FDA investigators physically visit and see firsthand how well

the company is doing.


For firms with more … “soft” …. approaches to compliance, a
remote or online/virtual inspection has less of a chance to
uncover gaps.

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

FDA is well aware of this.



In order to address this, expect FDA over the
next few years, to take a two-step approach to
an inspection:
◦ Part

one

is

a

remote

review

of

policies, SOPs, etc., (presumably through PDFs sent to
the agency);

◦ This will then inform and shape part two, the onsite
inspection.


1/6/2014

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

Management

discussion

items

are

non-

compliance observations not written onto the
Form FDA-483.


Management discussion items are compliance
deviations that the FDA investigator believes
to

be

of

lesser

significance

than

the

documented 483s.

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

Management discussion items can still end up as

warning letter citations because the FDA district
office or FDA head office believes they are more
serious than originally assumed.


Thus, if you address management discussion items in
your response to FDA, you may want to notify the
district that you are working to resolve the items as

well as the written 483 observations.

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

Keep in mind that to FDA, as long as an observation

of non-compliance was documented
◦ in the FDA investigator’s notes,
◦ written on a Form FDA-483, or
◦ spoken about to a firm's management,


FDA considers the observation “documented by FDA.”



FDA is, at its heart, an enforcement agency collecting

evidence when it conducts an inspection.

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

Management discussion items can be treated

as repeat violations if found again in a
follow-up or a second FDA inspection.


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

Technically, up to 45 days after the inspection.



In reality, depending on the type, depth, and other
FDA inspection conditions, it can be up to 3-6
months after the FDA investigator leaves.



Nonetheless, your FDA inspection response and
remediation plan is still due to the agency within 15
business days after departure of the FDA investigator.

1/6/2014

27



This presentation was compiled from freely
available resources like the websites of FDA
and other free websites.
 “Drug Regulations” is a non profit
organization which provides free online
 Visit http://www.drugregulations.org for
latest information from the world of
Pharmaceuticals.

1/6/2014

28

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