Data integrity nishodh 01092016

“USFDA, MHRA and other Guidance
on Data Integrity and
What it means to your Enterprise”
Dr. Nishodh Saxena1
19-09-2016Copyright @NishodhSaxena

DEFICIENCIES IN GMP DATA INTEGRITY AND DATA MANAGEMENT
• Shared passwords
• Lack of enabled audit trails
• Failure to review electronic data
• Failure to review and investigate all failed testing results
• Failure to contemporaneously record information
And Many More …………..
2

WHAT WILL YOU LEARN?
• The regulatory enforcement background
• The applicable regulations and guidance
• The enforcement actions taken by global regulatory
authorities
• What actions you can take within your own company to begin
to address the topic
And you will have links to the relevant references
3

WHAT WILL YOU TAKE AWAY?
• Data management that ensures integrity of the associated
data requires more than risk-based computer system
validations
It requires understanding of
• The events that precipitated this focus
• The intent of the governing regulations, guidance &
enforcement actions
• Will remove some of the mystery and provide background on
the topic of data management and data integrity and
suggestions for how they might begin to address this issue
within your company
4

REGULATORY ENFORCEMENT BACKGROUND
• The “generics scandal” of the 1980’s raised the issue of
falsified data submitted to FDA in support of drug approvals
FDA focus shifted from pre-approval inspection (PAI) to evaluate
raw laboratory data included in the marketing application and
evaluate whether the site was capable of manufacture as
described in the application
• This scandal also prompted implementation of the
Application Integrity Policy in 1991 which “describes the
Agency's approach regarding the review of applications that
may be affected by wrongful acts that raise significant
questions regarding data reliability ”
5

REGULATORY ENFORCEMENT BACKGROUND - APPLICATION INTEGRITY POLICY
6
APPLICATION INTEGRITY POLICY 2
1-1-1 Background 2
1-1-2 Purpose 2
1-1-3 Definitions 2
1-1-4 Education Program 4
1-1-5 Responsibilities Of Agency Personnel And Organization 5
1-1-6 Administrative Considerations 9
1-1-7 Revoking The AIP As It Applies To A Firm's Application(S) 13
1-2 ATTACHMENTS AND EXHIBITS 15

REGULATORY ENFORCEMENT BACKGROUND - APPLICATION INTEGRITY POLICY
LIST
• Five firms are on the current CDER Application Integrity Policy List
effective October 1, 2015 for deferring substantive scientific review
7
• CENTER FOR DRUG EVALUATION AND
RESEARCH
• CENTER FOR BIOLOGICS EVALUATION
AND RESEARCH
• Hill Dermaceuticals, Inc. • Sclavo, S.p.a.*
• Ranbaxy Laboratories, Ltd.
• CENTER FOR DEVICES AND
RADIOLOGICAL HEALTH
• Biopharmaceutics Inc.* • Bionike, Inc.
• Solopak Pharmaceuticals, Inc. • Bioplasty, Inc.*
• Superpharm Corp.* • Endotec, Inc.
• Micro Detect, Inc.
• Sherman Pharmaceutical, Inc.*
• Syntron
• CENTER FOR FOOD SAFETY AND APPLIED
NUTRITION
• Nil
• CENTER FOR VETERINARY MEDICINE
• Nil

• In parallel, FDA recognized the increased reliance on
computerized systems within the pharmaceutical industry
• They developed and published 21 CFR Part 11 , the final rule
on Electronic Records and Electronic Signatures in 1997
8

9
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICES
SUBCHAPTER A--GENERAL
PART 11ELECTRONIC RECORDS; ELECTRONIC SIGNATURES
Subpart A--General Provisions
§ 11.1 - Scope.
§ 11.2 - Implementation.
§ 11.3 - Definitions.
Subpart B--Electronic Records
§ 11.10 - Controls for closed systems.
§ 11.30 - Controls for open systems.
§ 11.50 - Signature manifestations.
§ 11.70 - Signature/record linking.
Subpart C--Electronic Signatures
§ 11.100 - General requirements.
§ 11.200 - Electronic signature components and controls.
§ 11.300 - Controls for identification codes/passwords.

• Electronic signatures were reasonably well understood
• Confusion remained regarding the interpretation and
enforcement of requirements for electronic records
• In 2003 FDA published a Guidance for Industry , Part 11,
Electronic Records; Electronic Signatures – Scope and
Application to address enforcement priorities
10

11
• In 2000, a warning letter issued to Schein Pharmaceuticals
cited lack of control over computerized laboratory systems
including lack of password control and broad ranging staff
authority to change data
• FDA issued a form 483 to Able Laboratories in New Jersey in
2005. Failing laboratory results were identified that were not
reported, and among the observations was failure to review
electronic data including audit trails
• Warning letters citing deficiencies in the broad area of data
integrity were issued to Actavis Totowa LLC site in the US, in
2007
• Three warning letters were issued to two Ranbaxy sites in 2006
and 2008

12
Telephone (973) 526-6004
February 1, 2007
REVISED WARNING LETTER
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Divya Patel, President
Actavis Totowa, LLC
101 East Main Street
Little Falls, New Jersey 07424
FILE NO.: 07-NWJ-06
Dear Mr. Patel:
On July 10, 2006, through August 10, 2006, the U.S. Food and Drug Administration
conducted an inspection of your facility located at 101 East Main Street, Little Falls,
New Jersey. During the inspection, our investigators documented significant
deviations from the current Good Manufacturing Practice (cGMP) regulations set forth
in Title 21, Code of Federal Regulations, Parts 210 and 211, in conjunction with your
firm's manufacture of prescription drug products.

13
Warning Letter
WL: 320-06-03
Via FedEx
June 15, 2006
Mr. Ramesh Parekh
Vice President, Manufacturing
Ranbaxy Laboratories Limited
Paonta Sahib, Simour
Himachal Pradesh 173 025 India
Dear Mr. Parekh:
We are writing regarding an inspection of your. pharmaceutical manufacturing facility
in Paonta Sahib, India, during the period of February 20-25, 2006. The inspection
revealed significant deviations from U.S. Current Good Manufacturing Practice
(CGMP) Regulations (Title 21 Code of Federal Regulations (CFR), Parts 210 and 211) in
the manufacture of drug products.

14
Warning Letter
Via FedEx
September 16, 2008
WL: 320-08-03
Mr. Malvinder Singh, CEO and Managing Director
Corporate Office
Plot 90, Sector 32,
Gurgaon -122001 (Haryana), INDIA
Dear Mr. Singh,
This is regarding an inspection of your pharmaceutical manufacturing facility in
Dewas, India by Investigators Thomas J. Arista and Robert D. Tollefsen during the
period of January 28 - February 12, 2008. The inspection revealed significant
deviations from U.S. current good manufacturing practice (CGMP) Regulations (Title
21, Code of Federal Regulations, Parts 210 and 211) in the manufacture of sterile and
non-sterile finished products. In addition, violations of statutory requirements, Section
501(a)(2)(B) of the Act, were documented with respect to the manufacturing and
control of active pharmaceutical ingredients (APIs).

15
Warning Letter
September 16, 2008
Via FedEx
WL: 320-08-02
Mr. Malvinder Singh, CEO and Managing Director
Corporate Office
Plot 90; Sector 32,
Gurgaon - 122001 (Haryana), INDIA
Dear Mr. Singh,
This is regarding an inspection of your pharmaceutical manufacturing facility,
Batamandi (Unit II), in Paonta Sahib, India by Investigator Jose R. Hernandez and
Chemist Susanna E. Ford, during the period of March 3 -7, 2008. The inspection
revealed significant deviations from U.S. Current Good Manufacturing Practice
(CGMP) Regulations (Title 21, Code of Federal Regulations, Parts 210 and 211) in the
manufacture of finished drug products.

16
• FDA announced a pilot program in 2010 to evaluate data
integrity as part of routine GMP inspections. FDA planned to
use the information gained from these inspections to
determine whether revisions to Part 11 or additional guidance
on the topic were necessary
• FDA stresses that they will “ continue to enforce all predicate
rule requirements, including requirements for records and
recordkeeping ”
• FDA found the problems were widespread during this pilot
evaluation, and enforcement actions in this area continue

APPLICABLE REGULATIONS AND GUIDANCE
17
• An official definition of “data integrity” is not found in the
regulations
• Expect that data will have attributes described in the acronym
ALCOA
• This acronym was first referenced in the September 2013 as
Guidance for Industry, Electronic Source Data in Clinical
Investigations and addresses the attributes of clinical “source
data.” As applied to GMP, that means data are expected to
be

18
Year Regulatory Development
1980 Generics Scandal
1991 Application Integrity Policy
1997 Regulation 21 CFR Part 11
2003 Guidance for Industry , Part 11, Electronic Records; Electronic Signatures –
Scope and Application
2010 FDA announced a pilot program to evaluate data integrity as part of routine
GMP inspections
2011 EMA revised and expanded Annex 11
2013 ALCOA-Guidance for Industry, Electronic Source Data in Clinical Investigations
Dec-13 MHRA expectation regarding self inspection and data integrity
Mar-15 MHRA GMP Data Integrity Definitions and Guidance for Industry
Sep-15 WHO GUIDANCE ON GOOD DATA AND RECORD MANAGEMENT
PRACTICES
Oct-15 Current Application Integrity Policy List
Jul-16 MHRA GxP Data Integrity Definitions and Guidance for Industry
Aug-16 PICS-GOOD PRACTICES FOR DATA MANAGEMENT AND INTEGRITY IN REGULATED
GMP/GDP ENVIRONMENTS
Aug-16 Q & As by EMA-23 questions on Data Integrity

19
Accurate Data must be accurate. Where appropriate,
correctness should be 2nd person verified. This
extends, for example, to data / information that are
presented in multiple locations such as an equipment
log, laboratory notebook, and electronic
chromatography data where data should be in
agreement.
Legible Data and results must be legible / readable. Electronic
data must also have the capability to be made human
readable.
Contemporaneous Thus, data are recorded at the time of the event /
action, not transcribed at a later date. Data are not
transcribed from post-it notes or scrap paper to the
official documents such as batch records or laboratory
notebooks.

20
Original Original data are similar to “raw data”. The following is taken from
the MHRA guidance and appears to also represent FDA’s opinion:
“Original record: Data as the file or format in which it was originally
generated, preserving the integrity (accuracy, completeness,
content and meaning) of the record, e.g. original paper record of
manual observation, or electronic raw data file from a
computerized system.” The paper print out of a chromatogram is
no longer considered the official raw GMP data because it does
not include the complete information, including but not limited to
meta-data, audit trails, and system configuration for the analysis in
question. FDA addresses this in their GMP Q&A.
Attributable This term requires the ability to determine who collected the data,
when it was collected, from which instrument it was collected and
who made any data modification or data manipulations. For
example, for HPLC chromatography, this includes all integration
events. Use of shared passwords renders makes it impossible for
the reviewer to attribute the data to a specific person.

21
• Following regulations that are most frequently cited in warning
letters
• 21 CFR 211.194 Maintenance of complete laboratory records
• 21 CFR 211.68 Adequate controls over computer systems
• 21 CFR 211.188 Production and control records shall include
complete information
• 21 CFR 100(b) Actions are documented at the time they are
performed

22
• EMA revised and expanded Annex 11 of their GMP Guide in
2011 to provide additional clarification for computer system
requirements
EUROPEAN COMMISSION HEALTH AND CONSUMERS DIRECTORATE-GENERAL
Public Health and Risk Assessment Pharmaceuticals Brussels,
SANCO/C8/AM/sl/ares(2010)1064599
EudraLex
The Rules Governing Medicinal Products in the European Union
Volume 4
Good Manufacturing Practice Medicinal Products for Human and Veterinary
Use
Annex 11: Computerised Systems

23
MHRA expectation regarding self inspection and data integrity
News and hot topics
16 December 2013
The MHRA is setting an expectation that pharmaceutical manufacturers, importers and
contract laboratories, as part of their self-inspection programme must review the
effectiveness of their governance systems to ensure data integrity and traceability.
This aspect will be covered during inspections from the start of 2014, when reviewing the
adequacy of self inspection programmes in accordance with Chapter 9 of EU GMP.
It is also expected that in addition to having their own governance systems, companies
outsourcing activities should verify the adequacy of comparable systems at the
contract acceptor.
The MHRA invites companies that identify data integrity issues to contact:
GMPInspectorate@mhra.gsi.gov.uk

24
MHRA GMP Data Integrity Definitions and Guidance for Industry
March 2015
Eudralex volume 4
Introduction: Data integrity is fundamental in a pharmaceutical quality system which
ensures that medicines are of the required quality. This document provides MHRA
guidance on GMP data integrity expectations for the pharmaceutical industry. This
guidance is intended to complement existing EU GMP relating to active substances
and dosage forms, and should be read in conjunction with national medicines
legislation and the GMP standards published in Eudralex volume 4.

25
Working document QAS/15.624 September 2015 Draft document for comment
GUIDANCE ON GOOD DATA AND RECORD MANAGEMENT PRACTICES
(SEPTEMBER 2015)
DRAFT FOR COMMENT
© World Health Organization 2015
Should you have any comments on the attached text, please send these to Dr
S. Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards
and Norms (kopps@who.int) with a copy to Ms Marie Gaspard
(gaspardm@who.int) by 30 November 2015.

26
MHRA GxP Data Integrity Definitions and Guidance for Industry
Draft version for consultation July 2016
Background
The way in which regulatory data is generated has continued to evolve in line
with the introduction and ongoing development of supporting technologies,
supply chains and ways of working. Systems to support these ways of working
can range from manual processes with paper records to the use of
computerised systems. However the main purpose of the regulatory
requirements remains the same; having confidence in the quality and the
integrity of the data generated and being able to reconstruct activities
remains a fundamental requirement.

27
PHARMACEUTICAL INSPECTION CONVENTION PHARMACEUTICAL INSPECTION CO-
OPERATION SCHEME
PI 041-1 (Draft 2) 10 August 2016
DRAFT PIC/S GUIDANCE
GOOD PRACTICES FOR DATA MANAGEMENT AND INTEGRITY IN REGULATED GMP/GDP
ENVIRONMENTS
© PIC/S August 2016 Reproduction prohibited for commercial purposes.
Reproduction for internal use is authorised, provided that the source is
acknowledged.
Editor: PIC/S Secretariat e-mail: info@picscheme.org web site:
http://www.picscheme.org

28
Now, European Medicines Agency's answers to frequently
asked 23 questions on Data Integrity, as discussed and agreed
by the Good Manufacturing Practice (GMP) / Good Distribution
Practice (GDP) Inspectors Working Group
The Q & As have now been published on their website in
August 2016
at http://www.ema.europa.eu/ema/index.jsp?curl=pages/reg
ulation/q_and_a/q_and_a_detail_000027.jsp#section16
An important statement in the guidance is that manufacturers
“… are not expected to implement a forensic approach to
data checking …”

INSPECTION OBSERVATIONS, WARNING LETTERS, WHO NOTICES OF CONCERN,
AND EU INSPECTIONS
29
Report Number EudraGMDP
Document
Reference
Number
MIA
Numbe
r
Site Name Site Address City Postcode Country Inspection
End Date
UK GMP 36736
Insp GMP
36736/1707035-
0003 - NCR
37171 HOSPIRA HEALTHCARE
INDIA PRIVATE LIMITED
PLOT NOS: B3-B4,
B5 (PART OF), B6
(PART OF), B11-
B18, SIPCOT
INDUSTRIAL PARK,
IRUNGATTUKOTTAI
SRIPERUMBUDUR IN-602 105 India 01-07-2016
DE_SH/NCS/API/0
1/2016
36996 Artemis Biotech (A
Division of Themis
Medicare Limited)
Industrial
Development
Area, Plot No. 1 &
5 Jeedimetla
Hyderabad 500 055 India 29-06-2016
DICM/INSP/SM-
MASA- PE010-
1216
36981 ALCOR, S.L. Poligono Industrial
del Henares, Juan
de Austria 142
Guadalajara 19004Spain 15-06-2016
INSP 2015-026-
0869333
36670 JINAN JINDA
PHARMACEUTICAL
CHEMI. CO LTD
No. 6121
Longquan Road
Zhangqiu,
Shandong
250200China 01-06-2016
MHRA and other EU authorities are published in Eudra GMDP

AND EU INSPECTIONS
30
WHO has published at least two Notice of Concern announcements in 2015

AND EU INSPECTIONS
31
WHO has published at least two Notice of Concern announcements in 2015

AND EU INSPECTIONS
32
Warning Letters from US FDA
FISCAL YEAR COMPANY COMMENT
2016 Unimark Remedies Limited Your firm routinely re-
tested samples without documented justification and deleted analytical data.
2016 Sri Krishna Pharmaceuticals Ltd. Your firm failed to ensure that laboratory records included complete data derived from
all tests necessary to assure compliance with established specifications and standards
2016 Emcure Pharmaceuticals Limited our firm failed to ensure that laboratory records included complete data derived from all
tests necessary to assure compliance with established specifications and standards
2016 Ipca Laboratories Limited Failure to have computerized systems with sufficient controls to prevent unauthorized
access or changes to data.
2015 Svizera Labs Private Limited This WHO Notice of Concern addressed deficiencies in documentation
Now
2015 Quest Lifesciences Pvt. Ltd. This WHO Notice of Concern addressed deficiencies in documentation in the GCP
clinical trials area
2015 GVK Biosciences The French Medicines Authority inspected this site in Hyderabad, India and identified
apparent data manipulations conducted in
2015 Apotex Research Private Li mited Data used to release product did not agree with the original data; “trial” injections were
identified; failure to document activities as they occurred; failure to investigate and
report OOS results
2015 Hospira S.p.A Chromatography systems did not have adequate controls to prevent deletion or
modification of raw data files; audit trails were not enabled for the “Test” folder and the
firm was unable to verify what types of test injections were made, who made them or the
date or time of deletion.

AND EU INSPECTIONS
33
2014 Apotex
Pharmachem
India Pvt Ltd.
Lack of raw data; batches were tested until they passed; OOS events were not reported nor were
they investigated.
2014 Tri farma S.p.A. The firm does not retain laboratory raw data; there is a lack of access control to computer
systems.
2013 Fresenius Kabi
Oncology
This represents the first warning letter to cite the FDASIA definition of adulteration to include
products made in a facility that “delays, denies or limits” an inspection; electronic data could be
altered or deleted; use of “test” or “trial” injections.
2013 Wockhardt Ltd Practice of performing trial injections before the “official” injection; documentation entries not
made as the activities were performed; HPLC data could be deleted from standalone
instruments.
2013 Wockhardt Ltd This letter was the second one in 2013 to cite the new FDASIA power to deem product
adulterated if they are manufactured at a site that “delays, denies or limits” an inspection;
investigators found batch records for 75 lots torn in half in the waste area; HPLC raw data files can
be deleted from the hard drive using the common PC login used by all analysts
2011 Cetero Research This untitled letter was issued to a firm located in the US that conducted BA/BE studies in support
of NDAs and ANDAs. As part of follow up, FDA sent a letter to the firms that contracted with
Cetero Research for BA/BE studies requesting specific information to establish validity of the
BA/BE information in the drug application. We also include one of the forms 483 .

AND EU INSPECTIONS
34
2009 Ranbaxy, Ohm Laboratories in
Gloversville NY
Analysts were given access to delete data, user account privileges were
inadequate
2008 Ranbaxy, Paonta Sahib Written records were signed by individuals who were not present in the facility on
the day of the signing;
2007 Actavis Totowa LLC, NJ Electronic data files are not checked for accuracy; data discrepancies between
electronic data and data documented in laboratory notebooks.
2006 Wockhardt Failure to maintain complete and accurate records is a repeat deficiency cited at
previous inspections; Logbook did not contain complete and accurate information;
data were not documented at the time of performance.
2006 Ranbaxy, Paonta Sahib Failure to maintain documentation of operation conditions and settings, nor were
complete raw data retained; SOP provides for discarding of data.
2005 Able Laboratories, Cranbury NJ The 15-page form 483 was among the early forms 483 addressing the broad
category of data integrity. The inspection resulted in withdrawal of ~ 50 ANDAs and
the firm is no longer in business.
2000 Schein Pharmaceuticals Warning letter to Schein Pharmaceuticals cites inadequate control over laboratory
computer systems including password control and authority to change data.

WHAT ACTIONS COULD FIRMS TAKE?
35
• Firms should not assign all computer and software system
responsibilities to the IT groups without engaging a
knowledgeable Quality Unit and other stakeholders as active
partners
• Data management that ensures security and reliability of the
data must be effectively incorporated into the
Pharmaceutical Quality System
• Part 11 is a regulation, just as Parts 210 and 211 are
regulations

36
• Computer systems should be appropriately developed,
qualified, tested and periodically assessed to ensure they
remain in a validated state
• As part of system validation / re-validation, firms should
perform gap assessments for each GXP computer system
against the requirements of Part 11
• Internal GMP audit programs should always incorporate
assessments of data integrity

37
• For the QC laboratories, specifically: Laboratory instrument
associated computer systems and other computer systems
should be identified, assessed for their risk to the GMP area,
requirements defined and validated appropriately. Periodic
evaluations should be performed and documented to ensure
they remain in a validated state
• Firms should ensure they are informed regarding current
regulations, guidance and the enforcement environment

38
THANKS

39
QUALITY IS THE RESPONSIBILITY OF EACH AND EVERY INDIVIDUAL OF THE ORGANIZATION.

Data integrity nishodh 01092016

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