FDA Regulatory
Expectations,
Warning Letters
and Trends
17th Annual
Computer and Software Validation
Conference
Oleg Trigub
Director, Global IT Quality
Covance Inc.
Oleg.Trigub@Covance.com
What is an FDA-483?
Start of the Warning Letter!
• The form used by FDA investigators
to record observations
o 483 observations are not violations
• The observed practices indicate
drug adulteration
FDA Warning Letter
• Official correspondence
o Notifies the highest-ranking known official
o Identifies serious violations of regulations
• Published on the FDA website
o Available for review by other agencies, businesses,
consumers, and the media
FDA Inspection Focus
Drugs must meet
standards for:
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Safety
Identity
Strength
Quality
Purity
Data
Integrity
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How do we
ensure quality of
our products?
Ensure Laboratory
controls
Failure to investigate
unexplained
discrepancies
Document and
follow processes
So, What is Data Integrity?
Contemporaneous
Recording
Original or a true
Legible
Attributable
Complete
copy
Data
Integrity
Consistent
Enduring
Accurate
Available
Just How Important is
Data Integrity to FDA?
• "Data integrity really sounds off
alarm bells for us ... if you see data
integrity on the surface, there is
likely a lot going on underneath.“
Thomas Cosgrove, director at the FDA's
office of manufacturing quality
FDA Draft Data Integrity Guidance
• Data Integrity and Compliance with CGMP –
Guidance for Industry, April 2016
o 21 CFR Parts 211 and 212 Requirements with respect to data
integrity include:
• 211.68 – “backup data are exact and complete,” and
“secure from alteration, inadvertent erasures, or loss”
• 212.110(b) – data be “stored to prevent deterioration or loss”
• 211.100 and 211.160 – activities be “documented at the time
of performance” and that laboratory controls be
“scientifically sound”
• 211.180 – records be retained as “original records,” “true
copies,” or other “accurate reproductions of the original
records”
• 211.188, 211.194, and 212.60(g) – “complete information,”
“complete data derived from all tests,” “complete record of
all data,” and “complete records of all tests performed”).
Draft Data Integrity Guidance Clarifications
• Reiterates and clarifies terminology
o Data Integrity
o Metadata
o Audit Trail
o “Static” and “dynamic” Record Formats
o Backup
o “Systems” in “Computer or Related
Systems”
Draft Data Integrity Guidance Clarifications
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Excluding CGMP data from decisions
Workflow Validation
Access Restrictions
Concerns with Shared Login Accounts
Controls for Blank Forms
Reviewing Audit Trails
Electronic Copies
Paper Printouts
Electronic Signatures
Electronic CGMP Record
Draft Data Integrity Guidance Clarifications
• It is NOT Acceptable to:
o Use Actual Samples in “System Suitability”
o Save the final results from Reprocessed Lab
Chromatography
o Informally Address Tips about Quality Issues
Draft Data Integrity Guidance Clarifications
• Training on Data Integrity
• Electronic Records subject to FDA
inspection
• Addressing data integrity problems post
inspection
MHRA Guidance for Industry on
Data Integrity (revised in March 2015)
• The guidance expects that
o The effort and resource assigned to data
governance is based on risk to product quality
o Companies have an overarching data governance
system
o Data integrity policies and staff training be
developed
• As well as verify the adequacy of comparable vendor
systems
MHRA Guidance for Industry on
Data Integrity (revised in March 2015)
• The guidance also expects that
o Consideration should be given to the organizational
and technical controls
• Procedures and computer system access
o Data reliance checks are early on in the inspection
• The result will determine whether the inspection will
continue normally or with a forensic approach
o Changes are being made to in EU GMP to the
definition of ‘Critical’ deficiency to include “data
falsification”
What are Data Integrity
Observation Categories?
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Maintain manufacturing and drug testing data
Ensure that Data is attributable to Specific People
Falsification and inaccurate data
Failure to complete documentation ‘contemporaneously’
Non-availability of raw data
Training file ‘re-written’
FDA Data Integrity Warning Letters
Dr. Reddy’s
Laboratories
“Failure to prevent
unauthorized access or
changes to data, and to
provide adequate
controls to prevent
omission of data “
Nov 2015
Agila Specialties Pvt
Ltd
“failed to exercise
appropriate controls over
computer or related
systems to assure that
only authorized
personnel can change
master production and
control records“
Aug 2015
24
• Since 2010, the FDA
has issued warning
letters to an
increasing number of
companies for Data
Integrity violations
o The FDA issued warnings to 10 drug
companies in 2015 for data integrity
violations – the most in at least 10 years.
5
2010-2012 2013-2015
DI Citations to Drug Manufacturing Companies
Trends of Violations
• FDA Food Safety and
Modernization Act
(FSMA)
• Food and Drug
Administration Safety
and Innovation Act
(FDASIA)
39.2
20.6
2010
2015
FDA Foreign Drug Quality Inspections
Increased Foreign Inspections
Geographic Locations of FDA Violations
6 Warning
Letters
1 Warning
Letter
68.8% of all FDA
global drug
quality
inspections
between 2010
and 2015 were in
the US
18 Warning
Letters
Industry Implications
Other Current FDA and MHRA Points of Interest
• EU’s General Data Protection Regulation
• MHRA Auditor Direct Access
• FDA’s Guidance for Mobile Medical
Applications
References
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http://www.gpo.gov/fdsys/pkg/FR-2009-08-11/pdf/E9-19107.pdf
http://www.fda.gov/ICECI/Inspections/IOM/ucm122530.htm
http://www.fda.gov/iceci/inspections/fieldmanagementdirectives/ucm096015.htm
http://www.fda.gov/MedicalDevices/default.htm
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2009/default.htm
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2008/default.htm
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM4
95891.pdf
http://www.fda.gov/ICECI/EnforcementActions/ApplicationIntegrityPolicy/ucm2005394.htm
http://www.fda.gov/downloads/MedicalDevices/.../UCM263366.pdf
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=820
http://www.accessdata.fda.gov/scripts/warningletters/wlSearchResult.cfm?qryStr=data%20integrity&we
bSearch=true
https://mhrainspectorate.blog.gov.uk/2016/04/01/2015-eu-gcp-inspectors-electronic-data-integrityworkshop/
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/412735/Data_integrity
_definitions_and_guidance_v2.pdf
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/448609/Good_manuf
acturing_practice_inspection_deficiencies_2013.pdf
http://www.gmp-compliance.org/eca_news_1740_rss.html
http://www.pharmtech.com/how-important-data-integrity-regulatory-bodies
http://www.raps.org/Regulatory-Focus/News/2016/02/10/24296/US-FDA-Inspections-in-China-AnAnalysis-of-Form-483s-from-2015/?_sm_au_=iVVQbVbkWVZsWb1H
http://www.cbronline.com/news/cybersecurity/data/european-parliament-approves-general-dataprotection-regulation-in-historic-privacy-ruling-4864721
http://www.pharmsource.com/quality-systems-data-integrity-among-most-frequent-problems-cited-bymhra/
FDA Regulatory Expectations, Warning
Letters and Trends
17th Annual
Computer and Software Validation
Conference
Oleg Trigub
Director, Global IT Quality
Covance Inc.
Oleg.Trigub@Covance.com