Presentation on data integrity in Pharmaceutical Industry

Data Integrity
pharmauptoday@gmail.com

- Definition & Basics
- Criteria for integrity of laboratory data
- Regulatory Requirements
- Barriers to Complete Data
- Possible data integrity problems
- Previous observations
- FDA Warning Letters – 2013
- FDA Warning Letters – 2014
- FDA 483’s related to data integrity
- EU – Non compliance Reports
- WHO - Notice of Concern
- Summary of Data Integrity issues
- Consequences
- Rebuilding Trust
- Conclusion
Contents

Definition of Data Integrity
• Integrity as being the quality or condition of being whole or undivided;
completeness.
• In the context of laboratory data integrity within a GMP environment, this can be
defined as…
―generating, transforming, maintaining and assuring the accuracy, completeness
and consistency of data over its entire life cycle in compliance with applicable
regulations.‖

Why is Data Integrity Important?
• Undermines the safety and efficacy and/or assurance of quality of the drugs that
consumers will take.
• Data integrity problems break trust.
• We rely largely on trusting the firm to do the right thing when no one is seeing.

Data Integrity – What Regulators See
• Not recording activities contemporaneously
• Backdating
• Fabricating data
• Copying existing data as new data
• Re-running samples
• Discarding data
• Releasing failing product
• Testing into compliance
• Not saving electronic or hard copy data

Criteria for integrity of laboratory data
• Attributable — who acquired the data or performed an action and when?
• Legible — can you read the data and any laboratory notebook entries?
• Contemporaneous — documented at the time of the activity
• Original — written printout or observation or a certified copy thereof
• Accurate — no errors or editing without documented amendments
• Complete — all data including any repeat or reanalysis performed on the sample
• Consistent — all elements of the analysis, such as the sequence of events, follow on and are dated
or time stamped in expected sequence
• Enduring — not recorded on the back of envelopes, cigarette packets, Post-it notes or the sleeves of
a laboratory coat, but in laboratory note books and / or electronic media in the CDS or LIMS
• Available — for review and audit or inspection over the lifetime of the record
Analytical scientists need to understand these criteria and apply them in their respective analytical
methods.

Regulatory Requirements

GMP Regulatory Requirements for Data Integrity
Derived from the laboratory data integrity definition and the applicable 21 CFR 211 GMP regulations there
are some of the following points:
• Instruments must be qualified and fit for purpose [§211.160(b), §211.63]
• Software must be validated [§211.63]
• Any calculations used must be verified [§211.68(b)]
• Data generated in an analysis must be backed up [§211.68(b)]
• Reagents and reference solutions are prepared correctly with appropriate records [§211.194(c)]
• Methods used must be documented and approved [§211.160(a)]
• Methods must be verified under actual conditions of use [§211.194(a)(2)]
• Data generated and transformed must meet the criterion of scientific soundness [§211.160(a)]
• Test data must be accurate and complete and follow procedures [§211.194(a)]
• Data and the reportable value must be checked by a second individual to ensure accuracy,
completeness and conformance with procedures [§211.194(a)(8)]

US FDA Regulatory Requirements for Data Integrity
Reference: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124787.htm

US FDA Regulatory Requirements for Data Integrity
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=11

FDA Regulatory Requirements for Data Integrity
Reference: http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm073837.htm

FDA Regulatory Requirements for Data Integrity
Reference: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124787.htm

European Council Regulatory Requirements
Reference: ec.europa.eu/health/files/eudralex/vol-4/annex11_01-2011_en.pdf

European Council Regulatory Requirements
Reference: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000027.jsp#section9

MHRA Regulatory Requirements for Data Integrity
Reference:
http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodManufacturingPractice/News/CON355490

Designing systems to assure data quality and integrity
Systems should be designed in a way that encourages compliance with the principles of data
integrity. Examples include:
• Access to clocks for recording timed events
• Accessibility of batch records at locations where activities take place so that ad hoc data recording
and later transcription to official records is not necessary
• Control over blank paper templates for data recording
• User access rights which prevent (or audit trail) data amendments
• Automated data capture or printers attached to equipment such as balances
• Proximity of printers to relevant activities
• Access to sampling points (e.g. for water systems)
• Access to raw data for staff performing data checking activities.

Schedule L-I: Drugs and Cosmetics (Third Amendment) Rules, 2008
Reference: http://www.drugscontrol.org/pdf/ScheduleL-I.pdf

Health Canada – Letter to stakeholders
Reference: http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/notice-avis-ltr-obligations-eng.php

Application Integrity Policy (AIP)
• The Application Integrity Policy is what FDA pulls up when it has questions about a
manufacturer’s electronic data.
• Electronic information includes everything, such as emails, adverse events reports,
complaints, batch records, and quality control records—everything that’s stored
electronically.
Reference: http://www.fda.gov/downloads/ICECI/EnforcementActions/ApplicationIntegrityPolicy/ucm072631.pdf

Barriers to Complete Data
However, data integrity and the lack of complete data over the record retention period can be
compromised in a number of ways, such as:
• Human errors
 when data is entered by mistake (an uncorrected fat finger moment),
 stupidity (not being aware of regulatory requirements or poor training) or
 willfully (falsification or fraud with the intent to deceive)
• Selection of good or passing results to the exclusion of those that are poor or failing
• Unauthorized changes to data made post-acquisition
• Errors that occur when data is transmitted from one computer to another
• Changes to data through software bugs or malware of which the user is not aware
• Hardware malfunctions, such as disk crashes
• Changes in technology, where one item is replaced when it becomes obsolete or no longer
supported, making old records unreadable or inaccessible.

Possible data integrity problems
According to the FDA, the following are possible data integrity problems in the laboratory
that have been observed in the past:
• Alteration of raw, original data and records (e.g., the use of correction fluid)
• Multiple analyses of assay with the same sample without adequate justification
• Manipulation of a poorly defined analytical procedure and associated data analysis in
order to obtain passing results
• Backdating stability test results to meet the required commitments
• Creating acceptable test results without performing the test
• Using test results from previous batches to substitute testing for another batch

Previous observations

Warning Letters - 2013

Failure to record all quality activities at the time they are performed.
a. On October 26, 2012, the investigator noticed that during an inspection of the packaging area
for (b)(4) #(b)(4) a production employee had recorded the final packed quantity of the batch in
Step (b)(4), even though the quantity was not yet known because the operator had not yet weighed
the batch.
Immediately after observing the incident, the investigator requested a copy of page 6 of the batch record
containing Step (b)(4) and was given a photocopy. A full batch record provided later that day did not
include the original page 6. Instead it included a new version of page 6.
b. The investigator observed at least two examples when a manufacturing step was recorded in the
batch record before it occurred:
i. The production operator had already recorded the start time for step (b)(4) for (b)(4) #(b)(4) as 12:15
PM on October 26, 2012, although it was still 11:00 AM when our investigator noticed this situation.
ii. For the (b)(4) # (b)(4), at approximately 11:00 AM on the same date, a production officer had already
recorded (b)(4) of (b)(4) used for (b)(4) the API (b)(4) in the (b)(4) at step (b)(4) in the batch production
record, although the (b)(4) step had not yet occurred. The (b)(4) had not been pre-weighed or otherwise
measured out in advance.
Reference : WL: 320-13-22 / Aarti Drugs Limited 7/30/13

Failure to record all quality activities at the time they are performed.
c. On October 27, 2012, our investigator noticed that a QC analyst was performing a Loss on Drying
(LOD) analysis for (b)(4) Lot # (b)(4) and had recorded the completion time as "(b)(4)" and total time
as "(b)(4)" in the usage log book for the LOD oven usage logbook although the step was not yet
completed.
d. The investigator observed that a QC analyst had recorded completion times of laboratory analyses
that had not yet occurred. Specifically, a Loss on Drying (LOD) analysis was performed for (b)(4) Lot
#(b)(4) and (b)(4) Lot #(b)(4) at approximately 10:55 AM.
The investigator noted that the analyst had already recorded the completion time as "(b)(4)" for
two (b)(4) samples and "(b)(4)" for one (b)(4)sample although the step was not yet completed.
Our investigator asked the analyst why he recorded the completion time for each of the three
samples if the step was still in progress.
The analyst did not offer an explanation. Moreover, our investigator also found that weights for these
three samples were recorded on blank pieces of paper and not directly onto the test data sheets.

Failure to maintain laboratory control records with complete data derived from all
tests conducted to ensure compliance with established specifications and
standards, including examinations and assays..
b. The inspection at this facility documented that there is no raw data for the related
substance preparation of (b)(4) testing for lots (b)(4) of (b)(4) USP and there is no raw
data for the standard and sample preparation for the residual solvent testing of the same
lots.
When weighing samples, reagents, and other laboratory materials, QC analysts write weight
values on small pieces of paper, transcribe the values onto the analytical worksheets, and
then destroy the original paper on which the weights are written.
This was reported to be a normal practice within the laboratory. Our investigator also
observed the practice of writing the weight values for samples on a small piece of paper
and not on the analytical worksheet. This is an inappropriate documentation practice.

We observed and documented practices during the inspection that kept some
samples, data and results outside of the local systems for assessing quality. This
raises serious concerns regarding the integrity and reliability of the data generated.
For example,
a. Our review of the Chromeleon and Empower II software found that your firm was testing
samples unofficially, and not reporting all results obtained. Specifically, ―test,‖ ―trial‖ and
―demo‖ injections of intermediate and final API samples were performed, prior to performing
the tests that would be reported as the final QC results.
b. Out-of-specification or undesirable results were ignored and not investigated.
c. Samples were retested without a record of the reason for the retest or an
investigation. Only passing results were considered valid, and were used to release
batches of APIs intended for US distribution.
d. Unacceptable practices in the management of electronic data were also noted. The
management of electronic data permitted unauthorized changes, as digital computer
folders and files could be easily altered or deleted.
Reference : WL: 320-13-20 / Fresenius Kabi Oncology Ltd 7/1/13

Failure to follow and document quality-related activities at the time they are
performed.
• During this inspection, your QC Chemist admitted that, under the direction of a senior colleague, he
had recorded false visual examination data in the logbooks for reserve samples. This QC Chemist
was responsible for multiple entries in the (b)(4) API logbooks.
• Your firm’s failure to prevent, detect, and rectify the falsification of your GMP documentation is
concerning. In response to this letter, describe your investigation into this misconduct and clearly
explain how you determined the extent of the data falsification. Describe the role of the senior
colleague who advised the QC Chemist during this incident. Also describe your plans for and
outcome of a thorough investigation into data integrity at your facility, both in documents produced
by the QC Chemist involved in this incident and by all other personnel at your site.
• Our inspection also found that your laboratory failed to take note of a trend in the total impurity test
results reported for this API. A striking number of the long term room temperature stability results
show a drop in the total impurities result (for the most recent test) regardless of whether that is the
12, 24, 36, 40 or 48 month test interval.
Reference : WL: 320-13-23 / Posh Chemicals Private Limited 8/2/13

Your firm failed to ensure that laboratory records included complete data derived from
all tests necessary to assure compliance with established specifications and
standards (21 CFR 211.194(a)).
• For example, your firm did not retain any raw data related to sample weights and sample
solution preparations for the HPLC assays of (b)(4) tablet batches (b)(4) and (b)(4) that
you conducted on July 18, 2012. In addition, you did not include those results in the
calculation of the final assay values. Instead, you repeated the analysis the next day using
a new set of sample solutions, and reported the retest results on the certificates of analysis
(COAs). Other examples were also noted during the inspection.
• In response to the FDA-483, you conducted a retrospective investigation and concluded
that the analyst realized he recorded the initial data incorrectly in the HPLC ―trial folder‖
instead of the regular folder. Thus, he repeated the test the next day using the same
sample solutions. However, your QC manager stated during the inspection that the initial
injections were trial runs, and that performing trial standard and sample analysis prior to
official analysis is a standard practice in your QC laboratory. Moreover, our review of the
final QC worksheet revealed that you prepared the new retest samples on July 19, 2012,
the day after you performed the trial injections. (Continued …)
Reference : WL: 320-13-17 / RPG Life Sciences Limited 5/28/13

Your firm failed to ensure that laboratory records included complete data derived from
all tests necessary to assure compliance with established specifications and
standards (21 CFR 211.194(a)).
• Our investigator also observed (b)(4) trial HPLC injections during the period of January 5,
2012 to November 16, 2012. Your response acknowledged that a number of these trial
injections involved sample testing. However, you provided no evidence that your firm
retained laboratory records and raw data associated with these sample tests.
• Additionally, during an audit of the data submitted in support of
the (b)(4) regarding (b)(4) tablets USP (b)(4) mg, our investigator requested to review the
electronic analytical raw data to compare the values for (b)(4) assay and degradation
products. However, your firm provided only the printed copies of the raw data because
your firm did not have the software program available to view the electronic raw data.

Your firm failed to exercise appropriate controls over computer or related systems to assure that only
authorized personnel institute changes in master production and control records, or other records (21
CFR 211.68(b)).
• For example, you analyzed (b)(4) API lot (b)(4) on February 14, 2011, at 2:55 a.m., and then
retested it at 2:05 p.m. using a new sample solution. You did not maintain any raw data associated
with the initial test.
• In your response, you stated that the retest was performed due to data deletion of the original
analysis. You concluded that the analyst misused the administrator password to delete and overwrite
the actual data logged in the audit trail. The ability of your analysts to alter and delete electronic
analytical data raises serious concerns regarding laboratory controls in place at your facility.
• During the inspection, our investigator also identified a backdated QC worksheet in the analytical
report of (b)(4)API raw material batch (b)(4). When your analyst affixed the related substance and
IR weight printouts to the Format for Blank Sheet for Printout (Format No. F2/QCD/F/026-00), he
signed and dated this worksheet as July 29, 2011. A second analyst, who reviewed this worksheet,
also signed and dated it as July 29, 2011. However, your QA department did not issue this
worksheet until July 31, 2011. Your analyst acknowledged during the inspection that he backdated
this worksheet on July 31, 2011.

CFR 211.68(b)).
• For example, you analyzed (b)(4) API lot (b)(4) on February 14, 2011, at 2:55 a.m., and then retested it at
2:05 p.m. using a new sample solution. You did not maintain any raw data associated with the initial test.
• In your response, you stated that the retest was performed due to data deletion of the original
analysis. You concluded that the analyst misused the administrator password to delete and overwrite the
actual data logged in the audit trail. The ability of your analysts to alter and delete electronic analytical
data raises serious concerns regarding laboratory controls in place at your facility.
• During the inspection, our investigator also identified a backdated QC worksheet in the analytical report
of (b)(4)API raw material batch (b)(4). When your analyst affixed the related substance and IR weight
printouts to the Format for Blank Sheet for Printout (Format No. F2/QCD/F/026-00), he signed and dated
this worksheet as July 29, 2011. A second analyst, who reviewed this worksheet, also signed and dated it
as July 29, 2011. However, your QA department did not issue this worksheet until July 31, 2011. Your
analyst acknowledged during the inspection that he backdated this worksheet on July 31, 2011.
• Your response stated that the analyst incorrectly dated the worksheet as July 29, 2011, instead of July
31, 2011, and that there was no intention to deliberately backdate the document. However, your response
contradicted your analyst’s backdating admittance during the inspection. In addition, your response did
not explain the reviewer’s signature which was also dated July 29, 2011. Backdating documents is an
unacceptable practice and raises doubt about the validity of your firm's records.

Your firm failed to follow written procedures for production and process control designed to assure that
the drug products you manufacture have the identity, strength, quality, and purity they purport or are
represented to possess, and to document same at the time of performance (21 CFR 211.100(b)).
• Poor documentation practices during in-process testing. Specifically, an operator
performed the in-process tablet (b)(4) testing for the (b)(4) mg tablet batch #(b)(4)without
the batch record or a manufacturing form to document the results contemporaneously. The
FDA investigator was informed that the pre-test and post-test weight values are
documented in the batch record located in a separate manufacturing room rather than in
the same room where the actual weights are measured. Moreover, your operator stated
that he records the two weights with (b)(4) significant figures into the batch record from
memory.
• Additionally, the investigator noticed that the balance used in production was not level,
which can result in inaccurate weights. The investigator asked how long the balance had
not been level, and you indicated that you would investigate the matter and respond to the
investigator. To date, you have not responded to FDA explaining your resolution of this
matter.
Reference : WL: 320-14-01 / Wockhardt Limited 11/25/13

Warning Letters - 2014

C.F.R. §211.68(b))
• Your firm failed to have adequate procedures for the use of computerized systems in the
quality control (QC) laboratory. Our inspection team found that current computer users in
the laboratory were able to delete data from analyses. Notably, we also found that the
audit trail function for the gas chromatograph (GC) and the X-Ray Diffraction (XRD)
systems was disabled at the time of the inspection. Therefore, your firm lacks records for
the acquisition, or modification, of laboratory data.
• Moreover, greater than (b)(4) QC laboratory personnel shared (b)(4) login IDs
for (b)(4) high performance liquid chromatographs (HPLC) units. In addition, your
laboratory staff shared one login ID for the XRD unit. Analysts also shared the username
and password for the Windows operating system for the (b)(4) GC workstations and no
computer lock mechanism had been configured to prevent unauthorized access to the
operating systems. Additionally, there was no procedure for the backup and protection
of data on the GC standalone workstations.
Reference : WL: 320-14-03 / USV Limited 2/6/14

Failure to maintain complete data derived from all laboratory tests conducted to ensure compliance
with established specifications and standards.
• Your firm failed to prevent raw data from being deleted from the Atomic Absorption
Spectrophotometer (AAS) used for elemental analysis testing.
• Specifically, our investigation found laboratory analysts had access to delete and overwrite
AAS raw data. This instrument did not have sufficient controls to prevent unauthorized
access to, changes to, or omission of data files and folders.
• This is especially concerning because our inspection uncovered only 38 raw data files on
the hard drive of the AAS, while analysts stated that the AAS had been used for over 400
analyses. Your firm failed to store the raw data elsewhere.
• Therefore, all AAS testing results for which no raw data exists are in doubt. Your firm’s
improper control over the laboratory records raises concerns about the quality of the APIs
your firm has released.
Reference : WL: 320-14-04 / Canton Laboratories Pvt. Ltd. 2/27/14

• Your firm lacked accurate raw laboratory data records for API batches shipped by your firm. The
inspection revealed that batch samples were retested until acceptable results were obtained. In
addition, your quality control (QC) laboratory failed to include complete data on QC testing
sheets. Failing or otherwise atypical results were not included in the official laboratory control
records, not reported, and not investigated. For example,
• A review of the Gas Chromatograph (GC) electronic records from July 13, 2013, for (b)(4) USP
batch #(b)(4)revealed an out-of-specification (OOS) result for the limit of residual solvents that was
not reported. However, the QC test data sheet included passing results obtained from samples
tested on July 14, 2013 and July 15, 2013. The inspection documented that your firm discarded
sample preparation raw data related to the OOS results. In your response you indicate that the
electronic chromatographic data and the weighing log books were available and reviewed during the
inspection. However, the raw data and sample preparation information used for the calculation of the
test results that were found OOS or disregarded were not in fact available for review.
Reference : WL: 320-14-11 / Apotex Pharmachem India Pvt Ltd. 6/16/14

• A review of the High Performance Liquid Chromatograph (HPLC) electronic records from July 3,
2013, for (b)(4)batch #(b)(4) revealed an Out-of-Trend (OOT) result. The sample preparation raw
data was discarded and not reported. A QC analyst indicated that these results were discarded due
to some small extra peaks identified in the chromatogram fingerprint and an unexpected high assay
result. The QC test data sheet reported two new results that were obtained from samples tested on
July 4, 2013 and July 5, 2013, using a different HPLC instrument.
• A review of the Karl Fischer electronic records from November 21, 2013, for (b)(4) EP batch
#(b)(4) revealed an OOS result that was not reported. The passing results reported on the data
sheets were generated from another sample tested an hour after the initial OOS results were
obtained on the same day, November 21, 2013.

Failure to record activities at the time they are performed.
• Specifically, your staff used ―finished product reports review data‖ worksheets to document critical laboratory
information days after the actual testing was performed. The worksheets reported observations from your firm’s
secondary reviewer, and next to each of these listed observations the analyst marked them as corrected. A
review of these worksheets revealed that your analysts did not always record data in the laboratory records in a
contemporaneous manner as noted in the following examples:
• (b)(4) USP batch #(b)(4) worksheet dated September 18, 2013, reports ―sample wt. taken wrongly." However,
the correction to the stability data sheet for this lot gives the appearance that sample weighing was performed
on August 10, 2013.
• (b)(4) USP batch #(b)(4) worksheet dated September 19, 2013, reports ―all tests completed but appearance not
reported.‖ However, the correction to the test record indicates the test was performed on September 15, 2013,
the date of the original testing.
• (b)(4)% batch #(b)(4) worksheet dated June 11, 2013, reports ―resolution b/t (b)(4) & (b)(4) in ID std not in
working std & it is (b)(4) not (b)(4).‖ However, the correction to the stability test data sheet for this lot gives the
appearance that the resolution was performed on June 9, 2013

Failure to manage laboratory systems with sufficient controls to ensure conformance to established
specifications and prevent omission of data.
• Our inspection revealed serious deficiencies related to your documentation practices, including
missing raw data. It is a basic responsibility of your quality unit to ensure that your firm retains the
supporting raw data that demonstrates your APIs meet specifications that they are purported to
possess.
• For example, during the inspection, our investigator found a chromatogram related to (b)(4), API in
the trash, dated October 15, 2013, which reported an additional chromatographic peak when
compared to the standard. During the inspection, your firm stated that the analyst discarded the
chromatogram because it was present in the blank injection. However, the analyst was unable to
retrieve the blank chromatogram from the system because it was overwritten by a subsequent
injection.
Reference : WL: 320-15-04 / Novacyl Wuxi Pharmaceutical Co., Ltd. 12/19/14

Failure to manage laboratory systems with sufficient controls to ensure conformance to established
specifications and prevent omission of data.
• In addition, the inspection documented that your firm made changes to integration parameters for the impurities
test without appropriate documentation or justification. Your firm relied upon hand written notes on a
chromatogram discovered in a drawer at the laboratory as the documentation for this change. Furthermore,
your firm implemented this change without an audit trail that would have captured the date of the change and
who made the change.
Other significant deficiencies noted in your laboratory system include:
a) Failure to have a written procedure for manual integration despite its prevalence.
b) Failure to use separate passwords for each analyst’s access to the laboratory systems.
c) Use of uncontrolled worksheets for raw analytical data in your laboratory.
d) Presence of many uncontrolled chromatograms, spreadsheets and notes of unknown origin found in a
drawer.
• The lack of controls on method performance and inadequate controls on the integrity of the data collected raise
questions as to the authenticity and reliability of your data and the quality of the APIs you produce.
Reference : WL: 320-15-04 / Novacyl Wuxi Pharmaceutical Co., Ltd. 12/19/14

Failure to document manufacturing operations at the time they are performed.
• When reviewing the entries in your (b)(4) use, cleaning, and maintenance logbook for the days immediately
prior to the inspection, our investigator found missing entries. Your operators stated that lines were left blank to
later add information about cleaning events that may have occurred during a previous shift.
• During the inspection, our investigator found other similar instances of missing data or belated data entry in
your manufacturing records. These practices are not consistent with CGMP.
• Operators acknowledged that there is no system in place to report these lapses in the documentation system;
documentation errors of this type did not require deviation investigations or notification to the Quality Unit.
• In addition, during the inspection, one of your quality unit employees presented the investigator with a batch
record containing his signature, stating that he had performed the review of this batch record.
• The employee later admitted that he had falsified this CGMP record and stated that he in fact had not
performed the review, despite having signed the batch record as the QA reviewer and having released the
batch. This data falsification and the record-keeping deficiencies described above raise doubt regarding the
validity of your firm’s records.
Reference : WL: 320-14-12 / Zhejiang Jiuzhou Pharmaceutical Co., Ltd. 7/9/14

483’s related to data integrity

483’s Related to Data Integrity
Reference : Ranbaxy Laboratories Limited – Toansa – Jan-2014

483’s Related to Data Integrity
Reference : Impax Laboratories Inc. – Jul-2014

EU – Non compliance Reports

EU Non Compliance Reports
Firm Name Observation
Smruthi Organics Limited Feb
2014
• There was no raw data available in the Quality control laboratory for the verification of
compendial analytical methods.
Smruthi Organics Limited Jan
2014
• Manipulation and falsification of documents and data were observed in different
departments ;
Medreich Limited – Unit V • 1 deficiency related to data falsification has been classified as "critical" .
IND-SWIFT LIMITED, Punjab;
Mar 2014
• It was not possible to confirm the validity of stability testing data. Several falsified and
inaccurate results had been reported in long term stability and batch testing.
• Discrepancies between electronic data and those results formally reported were
identified.
• Established processes to verify data accuracy and integrity had failed and there had
been no formal investigation raised by the company.
• The company provided commitments to address the data integrity concerns and initiated
a wider review of quality critical data. Additional discrepancies were identified in process
validation and release data.
• During on-going communications with the licensing authority regarding the data review,
the company failed to disclose data integrity issues for all products. No satisfactory
explanation was given for this discrepancy.

Zeta Analytical Ltd, UK; Jan
2014
• It could not be confirmed who had conducted the testing or when because of
discrepancies in the raw data; consequently staff competence could not be confirmed.
• Raw data were not being recorded contemporaneously nor by the performing analyst.
• Failed HPLC injections of QC standards in place to demonstrate the correct operation
of the HPLC were deleted, repeated many hours after the original analysis and re-
inserted into the analytical sequence without explanation invalidating the batch
data. The company provided commitments to address the data traceability concerns.
Seikagaku Corporation,
Japan; Apr 2014
• The critical deficiency concerns systematic rewriting/manipulation of documents,
including QC raw data.
• The company has not been able to provide acceptable investigations and explanations
to the differences seen in official and non-official versions of the same documents.
Renown Pharmaceuticals Pvt.
Ltd., Gujarat, India; Aug 2014
• Record integrity and veracity: some records were made up or altered.
• Defects on deviation recording and investigation.
• Lack of mechanisms to ensure integrity of analytical data.

North China Pharmaceutical
Group Semisyntech Co., Ltd,
China, Jan 2015
• Lack of data integrity in the QC laboratory (No access control, inadequate traceability
and archiving practices, no audit trail, no restriction on the deleting of data, etc.) and
falsification of the analytical results for residual solvents;
Zhejiang Apeloa Kangyu Bio-
Pharmaceutical Co. Ltd.,
China; Nov 2014
• The company failed to establish a procedure to identify and validate GMP-relevant
computerized systems in general.
• Two batch analysis reports for Colistin Sulfate proved to be manipulated.
• HPLC chromatograms had been copied from previous batches and renamed with
different batch and file names.
• Several electronically stored HPLC runs had not been entered into the equipment log
books. The nature of these data could not finally been clarified.
• Neither the individual workstation nor the central server had been adequately protected
against uncontrolled deletion or change of data.
• The transfer of data between workstations and server showed to be incomplete.
• No audit trail and no consistency checks had been implemented to prevent misuse of
data.
Hebei Dongfeng
Pharmaceutical Co., Ltd,
China; Sep 2014
• Data recording and integrity in the QC laboratory

Sri Krishna Pharmaceuticals
Ltd., Hyderabad, India, Dec
2014
1. Drug products failing to meet established quality control criteria are not rejected. In
particular:
a) analysts routinely use the PC administrator privileges to set the controlling time and date
settings back to over-write previously collected failing and/or undesirable sample results.
This practice is performed until passing and/or desirable results are achieved;
b) Analysts routinely perform ―trial‖ injections of sample aliquots prior to performing the
official/reported analysis. There are no documented sample preparation details for these
trial analyses. The results of these trial injections are not reported, and were found to
differ significantly from the subsequent reported results;
c) Analysts routinely perform ―trial‖ injections of sample aliquots prior to performing the
official/reported analysis. The resulting raw data chromatogram files were often found to
have been deleted and unavailable for review;
d) Analysts delete undesirable and/or failing results (entire sample sequences) and retest
samples until desirable results are achieved.

Taishan City Chemical
Pharmaceutical Co. Ltd.,
China, Nov 2014
• Insufficient securisation of the electronic raw data in the Quality Control laboratory (No
limitation of access levels, no restriction on the deleting of data, no audit trail, inadequate
traceability and archiving practises);
Fujian South Pharmaceutical,
China, Oct 2014
• The inspection team tried to verify some regulatory information requested during the
assessment of the dossier and reached the conclusion that fundamental GMP and
regulatory requirements such as loss of data integrity, combined with insufficient
management of data, change control system, supplier qualification, laboratory controls
as well as the accuracy of data submitted, were not adequately implemented/considered
because of a weakness of the QA system and regulatory affairs department;
• Severe GMP violations related to the implementation of sound computerised systems in
the quality control facilities were committed, that could lead/could have led to the
falsification of data. It was impossible to verify that the decision to approve raw material
and final API was based on valid and accurate data;

Wockhardt - NANI
DAMAN, India Oct 2013
• Quality Control deficiencies including; inadequate records, lack of specificity in analytical
methods, failure to investigate unknown peaks and non-compliance with MA details.
Wockhardt Limited, India,
Jun 2014
• The deficiency related to data integrity, deleted electronic files with no explanation, the
running of ―trial testing‖ prior to performing system suitability and the formal testing and a
loss of control of reconciliation of samples such as those used for additional testing could not
be traced.
Wockhardt Limited, Nani
Daman, India Oct 2014
• Issues were identified which compromised the integrity of analytical data produced by the QC
department. Evidence was seen of data falsification.
• A significant number of product stability data results reported in the Product Quality Reviews
had been fabricated. Neither hard copy nor electronic records were available.
• In addition issues were seen with HPLC electronic data indicating un-authorised manipulation
of data and incidents of unreported trial runs prior to reported analytical runs.
Wockhardt Limited,
Aurangabad, Jan 2015
• A critical deficiency was cited with regards to data integrity of GMP records, entries were
seen to be made when personnel were not present on site, documentation was seen that
was not completed contemporaneously despite appearing to be completed in this manner.

WHO – Notice of Concern

WHO – NOC : Microlabs, Hosur

Summary of Data Integrity issues

• Employees signing as completing manufacturing steps were not on
premises at the time the steps were completed
• Data was removed and new data was added
• Employee scraped off entries with hand-made tool
• Making up Batch records during an FDA inspection
BPR’s
• Making up Training records during an FDA inspection
• Firm had no CGMP training
Training
• Testing conducted late but recorded as being tested on time
• No samples available, however testing data was generated
Stability

• Employee used same sample for identity testing on a regular basis
• Unlabeled or partially labeled vials dumped down the drain
Samples
• Test results for one batch were used to release other batches
• Releasing product with known contaminants
• Repacking failed product without assessing impact of failure; Repacked product was released
• Data supporting test results was missing
Quality
control
• Growth on microbiological plates was observed and recorded as no growth
Microbiol
ogy

• Employee used same sample for identity testing on a regular basis
• Unlabeled or partially labeled vials dumped down the drain
Samples
• Test results for one batch were used to release other batches
• Releasing product with known contaminants
• Repacking failed product without assessing impact of failure; Repacked product was released
• Data supporting test results was missing
Quality
control
• Growth on microbiological plates was observed and recorded as no growthMicrobiology

• No raw data for Standard preparation
• No raw data for Sample weights
• No raw data for Sample solution preparation and sample dilutions
• Sample and reagent weights are written on small pieces of paper and
transcribed onto analytical worksheets Then, small pieces of paper were
discarded
• Destruction of raw data not meeting specification
• Missing raw data
• Re-writing laboratory notebooks
• Unjustified invalidation of data and re-testing without a laboratory investigation
• Raw data found in the garbage
RawData

• Pre / post dating of the records.
• Failure to use approved procedures.
• Recording / Signing for others
• Re-writing the records without authorization.
• Failure to report / document a discrepancy.
• Failure to retain raw data / records.
Documentation

• Out-of-specification or undesirable results were ignored and not
investigated
• – Re-testing without justification
• – Product released despite failing sterility testing
• – Failing or suspect HPLC assay results are overwritten
• Evidence did not support the reason to invalidate the dissolution test
results
• Dissolution data discarded with no investigation
InvestigationData

• HPLC integration parameters were changed and re-run until passing
results were obtained
• Audit trail function was disabled.
• Unofficial testing of samples with file names like test, trial, or demo
• There are no controls to prohibit unauthorized changes to electronic
data / inadequate access controls.
• Files were saved on personal computers instead of a network
• Sharing passwords / unauthorized access.
• Lack of security on electronic data systems.
• Failure to maintain back-up of electronic data.
ElectronicData

Consequences

Consequences of Data Integrity
• Loss of Trust
• Recalls
• Form – 483
• Warning or Untitled Letter
• Import Alert
• Injunction
• Seizure
• Application Integrity Policy Invocation
• Non-compliance Report
• Notice of Concern
• Loss of job
• Loss of business
• Loss of Money

Rebuilding Trust

Data Integrity – Rebuilding Trust
• Know the Regulations & Intensity of Data integrity
• Perform a GAP Analysis
• Determine the scope of the problem / Detect the integrity
• Implement a corrective action plan (global) & Prevent the Integrity
• Remove individuals responsible for problems from CGMP positions
• Complete a satisfactory inspection

GAP Analysis
• Perform GAP analysis by
brainstorming with cross
functional team to identify and
prevent the data integrity
issues.
Review
System
Identify gap
Change
control
process
Develop,
Training &
implement
ion
Implications
Recommen
dations

Detecting & Preventing Data Integrity issues
• Increase the frequency of review
• Do surprise / spot checks
• Have a procedure & check list for review mechanism
• Compare hand writing styles / signatures.
• Verify attendance / presence of the person.
• Verify the traceability & log book entries.
• Internal / external audits.
• Trend the observations & provide the training
ReviewSystem

• Define a clear policy / procedure on various activities (e.g.
Password policy)
• Have clear procedure and controls over the electronic data /
software administration.
• Cross check Privileges Vs. Job responsibilities.
• Check the adequacy of the procedures.
Policies&Procedures

• Strategic planning
• Determine the level of compliance that we are seeking
• Identify the weaknesses and strengths in our computerized
systems
• Conduct an inventory of our systems
• Determine if the system must comply with Part 11
• Conduct the assessment using a checklist or spreadsheet
• Provide documented justification if certain system are exempt
from Part 11
• Implement and execute a remediation plan
• Conduct the required follow-up as warranted.
Part11GAPAssessment

Conclusion

Conclusion
• The integrity of data generated by any regulated laboratory is a prime factor in
determining the credibility of that laboratory.
• The finding of a single instance where data integrity is compromised casts a shadow
over the whole of the data generated.
• Remember that inspections and audits can only sample, finding one instance of
falsification raises the question of how many more instances of non-compliances exist?
Therefore, ensuring data integrity is of major importance to analytical scientists,
managers and quality assurance of any organization, as the consequences of getting it
wrong are very costly and it will take a long time to rebuild regulatory trust.

Conclusion
• The extended FDA regulation and draft guidance now also impact the laboratory data
integrity issue, as failure to provide complete records means that any drugs are now
classified as adulterated under the new extension of the Food Drug and Cosmetic Act as
amended in 2012.
• Data integrity issue is prevalent globally and not merely India centric. If the pharmaceutical
industry in the country is engaged in the production of life-saving drugs then it cannot afford
to be negligent.
• We need to be careful and it is absolutely fair by global regulators to keep tabs on this.
• Therefore it is not that India pharmaceutical companies are targeted by the global regulators

Data Integrity Part II is continued …. as
Presentation on Chromatography Data System (CDS)
http://www.slideshare.net/skvemula/chromatography-data-system-cds-in-pharma

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