1. No category

How to withstand an FDA audit:
A primer for manufacturing facilities and
laboratories
Kazem Kazempour, PhD
President and CEO
Amarex Clinical Research
Topics to be discussed
• FDA audit Purpose & Why/Who/What?
• Types of audits/Actions, dealing with Findings, Dreaded 483
• FDA Audit: Are you next?
• Can we avoid/Reduce impact of an FDA Audit? How?
• Preparing for an audit, How and Who?
• Frequency of FDA audits? Who are the auditors?
• Dos and Don’ts in and FDA audit.
• Take-home Messages
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FDA Inspection:
An Intimidating Thought (1)
•
•
•
•
•
•
Why FDA auditing us?
What did we do wrong?
Are we in trouble?
….. Oops!
Are we ready?
How to prepare?
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FDA Inspection:
An Intimidating Thought (2)
What ever you do:
Don’t Panic
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Why does FDA Audit us (1)?!




To use the money paid for review
They like giving us a hard time
To show that they can
They like to travel at tax-payers’ expense
No. None of the above
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Why Does FDA Audit us? (2)
It’s the Law: FDA is responsible for assuring that:
a) The products it approves are safe and
b) Appropriately :
 Developed,
 Manufactured,
 Distributed, and
 Reported
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Why does FDA Audits us (3)?!
FDA wants Manufacturers to:


Comply with the regulations,
Measure the effectiveness of their quality
AND



Assure that company quality goals will be
routinely met,
Assure that adequate controls are in place;
Assure that products/processes conform with
specifications.
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Who/What Gets Audited by FDA?

Almost any Manufacturer/product that has something
to do with Food and Drug!

Prior to final decision on a marketing approval application
such as NDA/PMA/BLA



High Risk Product




Manufacturer (always)
Clinical sites and vendors (For Cause, random or high priority)
Used in vulnerable population, e.g. children, mentally challenged
Used in large populations, e.g., cardiovascular, asthma, allergies
New technology, unknown mechanism, e.g., stem cells, gene therapy
High Risk Process



Safety concerns at clinical sites, e.g., reports of too many SAEs
Special testing processes, e.g., new biomarker.
Inadequate process controls, e.g., bad SOPs, no self audits
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Audit Types and Actions: GMP/GLP/GCP



Process and logistics are similar across GXPs:
 Compliance with current regulations
 Data/information integrity (documentation)
 Personnel files, and
 Facilities
Actions are similar
 Issuing 483s
 Issuing Warning letters and other punitive actions
Inspectors have similarly trained:
 Educational background of Inspectors
 Experienced in your kind of operations
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FDA-483 form
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An FDA Audit: Are you next? (1)
The
FDA may conduct announced/unannounced
inspections for various reasons such as:





Routinely to verify data that has been submitted to the Agency
As a result of a complaint to the Agency [i.e., “for cause”]
In response to sponsor concerns or termination of the site
At the request of an FDA review division
Some classes of investigational products are identified as:
products of special interest
http://www.fda.gov/oc/ohrt/irbs/investigator.pdf
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An FDA Audit: Are you next?(2)
Announced




1-2 weeks notice
Inform about agenda (this may expand, based on evidence)
Usually 1-3 inspectors
Low-key affairs
For




audit, general pattern:
cause audits
May be no notice, inspectors just show up
Cause for audit notified, clear agenda may or may not
Usually 1-3 inspectors, may be accompanied by law
enforcement
Usually high-profile, intrusive and inconvenient
http://www.fda.gov/oc/ohrt/irbs/investigator.pdf
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What is Subject to FDA Audit?
Almost Everything
 Manufacturing processes (GMP)
 Laboratory processes (GLP)
 Clinical process (GCP)




Sites,
investigators,
Vendors
Safety Reporting processes (GRP)
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Can you Refuse an FDA Audit?(1)
Worst Possible
Idea!
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Can you Refuse an FDA Audit?(2)



Refusal of an FDA request for audit is illegal
This is the worst action one may take
If this action is taken, it could lead to:

For US based sites:




FDA raids with Department Of Justice (DOJ)/law enforcement (almost
always)
Suspension of all activities at a given location
Evidence of non-compliance with US regulations
For non-US sites:




Ban import of products made
Legal action against US agent
Withdraw all products from the site already in US market
Very hard next time
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Can you Avoid/Reduce impact of
an FDA Audit?
Yes, Always!
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How one can Avoid/Reduce the impact of
an FDA Audit? (1)

Stay prepared, by Conducting internal regularly
scheduled audits and Fixing the findings :







Give you confidence, with announce/un-announced FDA audit
Make employees/site prepared
Improve and better your document and the process
Reduce and remove sloppiness, carelessness
Help to fix things with no panic and in a controlled atmosphere!
Maintain high level of compliance
Keep up to date with current regulations (e.g., training)
You will be ahead by Conducting Internal audits and
Fixing the findings
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FDA Inspection:
An Intimidating Thought (2)
In your internal audits, be objective/critical, at the minimum
you need to have:







A clear understanding of the objectives,
The audit scope,
An audit routine schedule,
Assignment of responsibilities,
Objective/ Measurable evaluation criteria,
Corrective action policies,
Management review of results
Internal Audit is not for SHOW it is for REAL!
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Can Anyone do the Internal audit?
NO!!
The auditor, among other things, should have:
1.
2.
The support of the TOP management,
A thorough working knowledge of:





the manufacturing processes and controls,
how products are developed, QCed/Validated,
how changes are incorporated/controlled,
quality assurance principles that apply,
AND
the human relations aspect of auditing!
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How Frequent are FDA Audits? (1)

“The good news is” not frequent enough
Due to the fact that:





> 100,000 companies in pharma sector alone,
> 825,000 “healthcare” companies
About 20,000 INDs, 80,000 clinical studies,
200,000 investigators
Expansion and fluidity of industry
Constantly there are “New” players in new roles
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How Frequent are FDA Audits? (2)

“The bad news,” it is becoming more frequent

Based on Government Accountability Office (GAO)
finding:
 In 1998 GAO identified weaknesses in FDA’s foreign drug
inspection program.
 From 2002 to 2007, FDA inspected relatively few foreign
establishments each year (GAO reported).
 In 2008 GAO recommended that FDA increase inspections of
foreign drug establishments
 GAO demanded that and later on examined FDA’s progress in
 Conducting more foreign drug inspections, and
 Improving its information on foreign drug establishments.
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Some statistics on Frequency of
FDA Audits? (1)
Total number of FDA inspections of Foreign
Establishments, fiscal year 2007 through 2009
70
60
India
China
50
Germany
Italy
40
Canada
United Kingdom
30
France
Japan
20
Switzerland
Ireland
10
Expon. (China)
0
Fiscal year 2007
Fiscal year 2008
Fiscal year 2009
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Some statistics on Frequency of
FDA Audits? (2)
The top three most frequently inspected countries
by FDA
70
60
50
40
India
China
30
Germany
20
10
0
Fiscal year 2007
Fiscal year 2008
Fiscal year 2009
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Some statistics on Frequency of
FDA Audits? (3)
Total number of FDA
inspections - 2007
Total number of FDA
inspections - 2008
6%
India
7%
6%
China
7%
Germany
8%
11%
France
11%
14%
7%
United Kingdom
10%
Germany
Italy
7%
Canada
7%
25%
6%
Italy
10%
6%
India
China
26%
9%
4%
13%
Canada
United Kingdom
France
Japan
Japan
Total number of FDA
inspections - 2009
India
5%
6%
6%
18%
China
Germany
8%
Italy
16%
10%
11%
11%
9%
Canada
United Kingdom
France
Japan
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Some statistics on Frequency of
FDA Audits? (4)
Percent of establishments in
FDA's inventory that may
never have been inspected
5%
Number of establishments in
FDA's inventory that may
never have been inspected
China
15%
India
12%
Canada
11%
France
Japan
15%
69
Germany
11%
7%
7%
9%
8%
Mexico
China
82
United Kingdom
South Korea
57 55
India
Canada
97
811
99
France
Japan
Italy
Germany
107
United Kingdom
South Korea
206
Mexico
323
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Italy
25
Some statistics on Frequency of
FDA Audits? (5)
Total number of inspections
Fiscal year 2009
70
60
India
50
China
40
Germany
Canada
30
United Kingdom
20
Italy
France
10
Japan
Ireland
0
Switzerland
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Some statistics on Frequency of
FDA Audits? (6)
Number of registered establishments
600
500
400
China
India
Canada
300
United Kingdom
Germany
200
France
Italy
100
0
China
India
Canada
United Germany
Kingdom
France
Italy
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Some statistics on Frequency of
FDA Audits? (6)
Number of BE site inspection requests
(2001-2010)
250
200
150
Clinical only
Analytical only
100
Total
50
0
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
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Some statistics on Frequency of
FDA Audits? (6)
For 2011 the planned audits and will be planned audits are:
1. Total of 254 Foreign Facilities Requiring a Preapproval
Inspection (PAI):
a. 62 are planed
b. 192 are in process to be planed
2. Total of 86 Domestic Facilities Requiring a Preapproval
Inspection (PAI):
a. 47 are planed
b. 39 will be planed
Planned PAIs for
2011
Pending PAI as
of 25-JAN-2011
Domestic
47
39
Foreign
62
192
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Where is FDA anyway?!
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Key Regulations




Good Manufacturing Practices: 21 CFR
211, 21 CFR 820
Good Laboratory Practices: 21 CFR 58
Good Clinical Practices: 21 CFR 312 and
ICH E6
Compliance Program Guidance Manual
http://www.fda.gov/ora/ftparea/compliance
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Who are the FDA auditors/Inspectors?

Enforcement arm of the FDA:





Office of Compliance, Division of Scientific
Investigations
The Bioresearch Monitoring (BIMO) program
More than 1000 auditors; who work for FDA
head-quarters (Washington DC area) or in
regional offices
All are trained in FDA auditing manual
All are experienced in fraud detection
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What constitutes Misconduct?

From an Auditor point of View:


If it is not documented it wasn’t done,
if it’s written but not done it is fraud
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What constitutes Misconduct?

Recognizing Research Misconduct, and
Falsification of data


Research misconduct means Falsification of
data in proposing, designing, performing,
recording, supervising or reviewing research, or
in reporting research results.
Falsification of data includes creating, altering,
recording, or omitting data in such a way that
the data do not represent what actually
occurred.
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FDA Enforcement Policy(1)

To maximize enforcement resources,
works with:





Generally Enforcement is based on:



Local,
State,
Federal, and
International health officials
Science,
Practical logic
Compliance with regulations is expected
and it is a MUST.
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FDA Enforcement Policy(2)

The industry is constantly monitored and given
opportunity to correct/prevent violations

Generally, the enforcement actions are metered
to the severity of violation, however:


Zero tolerance for fraud,
Zero tolerance for intentional violation or gross
negligence
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Some compliance Basics

Site Organization and Personnel





Facilities






Qualified personnel
Training, safety, management
Quality Assurance
Distribution of responsibilities
Visiting area, Access control
Equipments and procedures
Documentation and training (SOPs, manuals, etc)
Site management
Safety Procedures
Record Retention and Storage
21 CFR 312
ICH E6
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The FDA Investigator is here!
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So, FDA contacted you…



Being selected for audit by FDA does not
necessarily imply fault on your part
Almost all audits are study/application specific
Be courteous and professional


FDA auditor is doing his/her job
Most FDA audits are scheduled about 1-2
weeks in advance


Surprise audits do occur
1-2 weeks notice could be a surprise for you if you
are not prepared
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Before FDA visits (1)

Contact the relevant personnel




Inform them of the pending audit
Consult if you need with a consultant
Make a Plan, if there is none
Do a thorough check of documentation



Organize and clean-up
Documentation and process review
All internal audit findings (QC and QA
issues)
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Before FDA visits(2)

Prepare staff

Mock interviews

Two questions and a request:





What do you do?
How do you do the work?
Show me
Assign responsibilities for interacting
Trouble-shoot

Identified issues and their potential
resolution
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FDA Inspection: Dos and Don’ts (1)

Access should be controlled
1.
2.
3.
4.
5.
6.
7.
8.
Inspector announces himself/herself
Wait in reception area
QA/Regulatory personnel escort to designated area
Check credentials, never try to copy (its illegal)
FDA 482 presented, documents requested
Introductions and orientation, hospitality
Always escort to all the areas of the company that
he/she wants to visit/examine
Personnel access to be controlled and recorded
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FDA Inspection: Dos and Don’ts(2)

Make readily accessible: All documents
requested





Make readily accessible: Facilities




SOPs, manuals
Training files
Raw data access (Labs)
Relevant documentation
Manufacturing areas
Equipment suites
Labs and Clinics
Be available, make senior management aware
of progress
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FDA Inspection: Dos and Don’ts(3)


Take good notes, everything is being
recorded
Keep everyone calm





People get nervous and defensive
Train people to only say what they know
not what they believe
Never make unsubstantiated comments
If you don’t know, say so, don’t make up!
Good hospitality and personable people
make the process flow better
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FDA Inspection: Final Minutes

Exit interview




Summarize findings
Clear any misimpressions
Document discussions
FDA Inspector has two options


No findings (you are very good!!)
Findings (FDA 483)




Nobody’s perfect, don’t get shocked
Don’t argue or get defensive
Respond in writing at a later date
FDA 483 and your response becomes
public information
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Common Audit Findings (from 483s)

Documentation issues







Safety Reporting violations
Inadequate training records
Violations of site procedures (SOPs, training,
etc)
Protocol violations, e.g., Inclusion/exclusion
criteria violations
Procedural violations


Inadequate SOPs
Poor records
Study processes inadequately followed
Source document and CRF mismatch
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Take-home Messages


Don’t panic for announced/unannounced AUDIT
Develop a comprehensive/unified process for:







Record keeping,
Complaints,
Corrective action,
Reporting
Establish process and schedule for Internal
Audits
Take the Internal finding seriously, and
Fix the internal findings as if they are from FDA
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Take-home Messages (2)
View the Audit as a free
Consultation
from FDA!!
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FDA Inspection:
An Intimidating Thought (3)
First time was 1995 that as head Biometrics/QA/QC I
was responsible for an FDA Audit.
……
..100s FDA meetings including audits/dsmb…
……
Last time was 2010 as President CEO I was
responsible for an FDA Audit. !
Always no panic, always respectful, and always
looking at the audit as an opportunity!
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References:
1.
Richard L. Friedman, Director, Division of Manufacturing and Product Quality Office of Compliance; CDER
Update, March 15-17, 2011.
2.
DEPARTMENT of HEALTH and HUMAN SERVICES, Food and Drug Administration (FY 2012 Online
Performance Appendix)
3.
Many ICH, many 21 CFRs such as: 21 CFR 211, 21 CFR 820, 21 CFR 58, 21 CFR 312 and ICH E6
4.
United States Government Accountability Office (GAO) Report to the Committee on Oversight and
Government Reform, House of Representatives , September 2010
5.
46832 NDA Pre-Approval Inspection/Methods validation (5/12/2010)
6.
Inspection of Cosmetics: An Overview, May 4, 2010
7.
Guidance for Industry, FDA Staff, and Third Parties, Accreditation Criteria Document issued on: August 6, 2009.
8.
Good Manufacturing Practice (GMP) Guidelines/Inspection Checklist ,(April 24, 2008),
9.
Inspection of Cosmetics: An Overview, February 25, 2003;
10. Good Manufacturing Practice (GMP) Guidelines/Inspection Checklist , (February 12, 1997),
11.
Guidance for Industry, Q7A Good Manufacturing, Practice Guidance for Active, Pharmaceutical Ingredients
12. And obviously online information/statistics from http://www.fda.gov
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This Seminar is Brought to you by
Amarex Clinical Research
Washington DC metro area
A Product Development Services Company
From Lab to Market Approval
FDA Meetings
Global Regulatory Submissions
Global Clinical Trials
Statistics & Data management
Strategy Implementation
Pre-Clinical Assays
Contact: Patrick Burke at [email protected] 301-528-7000
www.amarexcro.com
Thank You!
Questions and Comments
Kazem Kazempour, PhD
President and CEO
Amarex Clinical Research
Germantown, MD 20874, USA
[email protected]
www.amarexcro.com
001-301-528-7000 (ext 777)
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