Bioscience Solutions
Data Integrity for Endotoxin Testing
FAQs Tech Tip
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Recently, a number of major data integrity observations have been
found by regulators during GMP inspections.
Some types of data integrity observations:
–– Alteration of raw, original data and records
–– Multiple assays with the same sample without adequate
justification
–– Manipulation of a poorly defined analytical procedure or the
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
Therefore, due to these observations, auditors have become trained to
perform more stringent inspections, and various global regulatory bod-
ies have recently published guidance documents on the overall data
lifecycle. In the interest of time, instead of a thorough dissection and
debate on individual documents, it is evident there is consistent lan-
guage across them, and systems need to follow the superset of all of
the requirements. For this discussion, we’ll focus on the the simplified
requirements and what they mean. In addition, we address how these
requirements relate to the in-process and endotoxin release testing, and
how the use of a full kinetic system such as WinKQCL™ Kinetic Endotoxin
Detection System can support full compliance for data integrity in endo-
toxin testing.
Tech Tip
What is Data Integrity?
“…refers to the completeness, consistency, and accuracy of data.” US
FDA Draft Guidance to Industry “Data Integrity and Compliance With
CGMP Guidance for Industry” (4/2016)
Data integrity is the degree to which a collection of data is complete, con-
sistent and accurate throughout the data lifecycle. The collected data
should be attributable, legible, contemporaneously recorded, original or
a true copy, and accurate. Assuring data integrity requires appropriate
quality and risk-management systems, including adherence to sound
scientific principles and good documentation practices. (WHO Guideline
Good Data and Record Management Practices)
Data integrity addresses:
–– Segregation of duties
–– Validation for intended use
–– Data and metadata review
–– Bad practice if corporate governance is instilled
What is Raw Data?
Raw data refers to original records and documentation, retained in the
format in which they were originally generated (i.e. paper or electronic),
or as a ‘true copy’. Raw data must be contemporaneously and accurately
recorded by permanent means. In terms of endotoxin detection soft-
ware, your raw data would be your electronic data. There is a misconcep-
tion that if you generate a print out and stamp it, the printout becomes
the raw data. In fact it is merely a “true” copy of the original.
What is Metadata?
Metadata is the data about data and describes the attributes of other
data. Typically, these are data that describe the structure, data elements,
interrelationships and other characteristics of data. Metadata provide
context and relationship to the primary data thus preserving the accu-
racy, completeness and content (MHRA). Without metadata, the data
has no meaning (MHRA).
In an endotoxin test, your metadata would include lot and serial numbers
for the reagents and accessories, i.e. ancillary products, and equipment
used in the process to obtain your final result.
What is ALCOA?
ALCOA Paper Electronic
Attributable Entries signed by the person Validated electronic signatures
making the recording Individual log-ins
Audit trails
Legible Ink, no pencil, no correction Controls over data deletion
fluid, rules on crossing out, etc. Back-up/archiving
Archiving
Contemporaneous Manually documented Automatically documented
Original Original records kept! Original electronic data and
metadata are kept
Accurate Calibration, maintenance,
validation of instruments
How Does Data Integrity Affect Endotoxin Testing?
The Bacterial Endotoxins Test is a critical test for potential contamination
of injectable drugs and medical devices. It is a mandatory release test
for batch production of therapeutic products. As such, it features often as
a key part of US FDA inspections across the world. Whilst it is possible to
release products on the final release test alone, increasingly the US FDA
is looking for ‘Control of Process’ and solid data integrity measures as a
better means of protecting patients. For example, this means that the
final product release using gel clot alone is regarded as not well suited to
providing the necessary data due to both the manual data recording and
the lack of trending /auditing information.
Is Gel Clot Testing Sufficient for Data Integrity?
It must be stressed that the gel clot assay is perfectly acceptable as an
end product release test and it remains a mainstay compendial method.
However, in countries with developing pharmaceutical industries, the
concern is that often companies use the gel clot assay on final prod-
uct release testing alone, or with very limited process controls. Modern
2   Bioscience Solutions– Data Integrity for Endotoxin Testing FAQ
trends are to build quality into the final product with testing throughout
the entire manufacturing process. In a well-controlled process, the re-
lease test then becomes a confirmation of the final product quality and
not an attempt to detect a contaminated batch with an assay that is not
statistically valid.
In gel clot testing, final product release based on the testing of end-
product provides very limited information and in the end, is statistically
meaningless. It provides minimal information about the manufacturing
process in terms of potential contributors to the total endotoxin load or
the effectiveness of any depyrogenation stages. There is also no infor-
mation available about underlying endotoxin trends. It is very difficult
to provide this sort of vital information with a qualitative test, hence the
need for quantification. A quantitative system can provide the manufac-
turing plant with information at an early stage that can prevent costly
problems further on in the manufacturing process. Trending data can
provide early indication of potential risks to the process.
Data integrity limitations when using the gel clot assay may include:
–– Actions may be missed in following your SOP
–– Dependence on proper transcriptions for each step
–– Forms may have missing items or omitted transcription
–– Results can be easily misinterpreted if not trained correctly
(subjective)
–– Much easier to manipulate if a second person reviewer is not
present
–– Ability to trend data is reduced
–– There is a requirement to use validated spreadsheets for calculating
final results
–– Difficulties in creating an audit trail and setting up an associated
review process based on criticality
–– Potential for mistakes is great, leading to a higher chance for
deviations
–– Much longer investigations and potentially more costly
–– Resources are tied up in investigations
–– Increased risk of expensive batch failure due to the lack of visibility
of developing trends
What Are the Key Advantages in Using a Quantitative
Endotoxin Detection System vs. a Qualitative System
With Respect to Data Integrity?
The main advantage of a quantitative method is that it provides informa-
tion about what is happening in a manufacturing process in an electronic
form. It also provides important information about underlying endotoxin
trends that are invisible using a qualitative method. This is what allows
us to use the trending feature so effectively. We must also keep in mind
that the inherent system controls and software used is fully 21 CFR Part
11 compliant; this makes it easy to control and access data in an elec-
tronic format.
If software is compliant, it will automatically include an audit trail that
will record many of the key issues that concern regulators looking for
established data integrity rigor. To be fully secure for example, the data
collected must be held in an encrypted database that cannot be altered
without that fact being recorded in the audit trail. Trending of results can
also help to show what the underlying status is for endotoxin in your
product.
WinKQCL™ Kinetic Endotoxin Detection System incorporates three ele-
ments and offers a fully integrated quantitative solution:
–– Kinetic-QCL™ Kinetic Chromogenic LAL Assay or PYROGENT™-5000
Kinetic Turbidimetric LAL Assay
–– WinKQCL™ Endotoxin Detection and Analysis Software
–– Incubating absorbance plate reader
For WinKQCL™ Endotoxin Detection and Analysis Software, a 21 CFR Part
11 compliance document is available upon request that compares 21
CFR Part 11 requirements to the integrated WinKQCL™ Software features
and end-user responsibilities.
WinKQCL™ Endotoxin Detection and Analysis Software offers:
–– Identification of raw data
–– Data storage/archiving/migration
–– Interfacing structure (exporting to LIMS, MODA)
–– Levels of user access
–– Electronic signatures
–– Audit trail
–– Edits/changes documented clearly and visibly
–– Records of assays started but not completed
–– Trending tools
–– Evidence of audit trail review – assigning criticality
–– 21 CFR Part 11 compliance document
What Are the Unrealized Costs When There Are Data
Integrity Risks in the Endotoxin Testing Process?
The logic of not switching from gel clot to kinetic testing is often based on
short-term costs: focusing on the cost of reagents, the cost of readers,
the cost of maintenance, the cost of training, the cost of re-validation
etc. But what is truly the cost of NOT converting? A number of potential
high-cost consequences need to be considered:
–– What is the cost of failing an internal or external audit due to not
having the extraneous controls in place that are inherent within an
electronic system and company policy?
–– What is the cost of receiving a 483?
–– The cost of plant shut-down?
–– The cost of batch hold?
–– The extra warehousing cost?
–– The cost of an OOS/OOT investigation
–– The cost due to delays because of revenue recognition?
–– The cost of batch scrappage?
–– The cost of campaign delays: you cannot produce the future
3   Bioscience Solutions – Data Integrity for Endotoxin Testing FAQ
batches because you are still holding and investigating the previous
failure?
It is questions like these that must be considered.
How Does WinKQCL™ Endotoxin Detection and Analysis
Software Ensure Data Integrity?
Data integrity is assured when a fully compliant endotoxin detection
software program is enveloped in a corporate-wide responsibility to
ensure uncompromising data integrity practice. Meaning, the company
institutes and educates all personnel on practices to promote the moral
and ethical considerations to follow a data integrity rigor. By understand-
ing the process/workflow and not just the software alone, standard op-
erating procedures can ensure risk is reduced.
Does WinKQCL™ Endotoxin Detection Software Have
the Tools Needed to Enforce Data Integrity Guidelines?
The combination of electronic data controls, audit trail review and trend
analysis, provides a clear view of what is happening in the workflow pro-
cess with the sample in mind. Regulatory agencies are actively looking
at the degree of control that companies have over their manufacturing
processes. It is much easier to control and to demonstrate control over
potential contamination with endotoxin using quantitative methods.
Using a fully compliant endotoxin detection software package such as
WinKQCL™ Endotoxin Detection and Analysis Software, will provide the
necessary tools to be compliant with data integrity regulations and re-
quirements.
Please contact scientific.support@lonza.com for more information on
how we can meet your data integrity expectations for performing the
endotoxin tests.
References
1. Data Integrity and Compliance With cGMP Guidance for Industry Draft
Guidance (April 2016)
http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/
documents/document/ucm495891.pdf
2. MHRA GMP Data Integrity Definitions and Guidance for Industry
(March 2015)
https://www.gov.uk/government/uploads/system/uploads/attach-
ment_data/file/412735/Data_integrity_definitions_and_guidance_
v2.pdf
3. WHO Guideline Good Data and Record Management Practices
(June 2016):
http://www.who.int/medicines/publications/pharmprep/WHO_
TRS_996_annex05.pdf?ua=1
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4   Bioscience Solutions – Data Integrity for Endotoxin Testing FAQ