Professional Documents
Culture Documents
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 483s related to data integrity
- EU Non compliance Reports
- WHO - Notice of Concern
- Summary of Data Integrity issues
- Consequences
- Rebuilding Trust
- Conclusion
Contents pharmauptoday@gmail.com
Definition of Data Integrity
In the context of laboratory data integrity within a GMP environment, this can be
defined as
Undermines the safety and efficacy and/or assurance of quality of the drugs that
consumers will take.
We rely largely on trusting the firm to do the right thing when no one is seeing.
Data Integrity What Regulators See
Backdating
Fabricating data
Re-running samples
Discarding data
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
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
MHRA Regulatory Requirements for Data Integrity
MHRA Regulatory Requirements for Data Integrity
MHRA Regulatory Requirements for Data Integrity
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
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
manufacturers electronic data.
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
Using test results from previous batches to substitute testing for another batch
Previous observations pharmauptoday@gmail.com
Warning Letters - 2013 pharmauptoday@gmail.com
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.
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.
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.
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 firms 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.
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.
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.
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.
Reference : WL: 320-13-17 / RPG Life Sciences Limited 5/28/13
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.
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 analysts backdating admittance during the inspection. In addition, your response did
not explain the reviewers 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.
Reference : WL: 320-13-17 / RPG Life Sciences Limited 5/28/13
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)).
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 pharmauptoday@gmail.com
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
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 firms
improper control over the laboratory records raises concerns about the quality of the APIs
your firm has released.
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.
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.
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 firms
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
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.
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.
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 firms records.
Test results for one batch were used to release other batches
Quality Releasing product with known contaminants
control Repacking failed product without assessing impact of failure; Repacked product was released
Data supporting test results was missing
Test results for one batch were used to release other batches
Quality Releasing product with known contaminants
control Repacking failed product without assessing impact of failure; Repacked product was released
Data supporting test results was missing
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.
Consequences pharmauptoday@gmail.com
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 pharmauptoday@gmail.com
Data Integrity Rebuilding Trust
Review
Perform GAP analysis by System
issues.
Change
Implications control
process
Develop,
Training &
implement
ion
Detecting & Preventing Data Integrity issues
Review System
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
Detecting & Preventing Data Integrity issues
Strategic planning
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
pharmauptoday@gmail.com
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