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Lessons from Pharmaceutical Laboratory
related FDA Warning Letters
Ludwig Huber
The Agilent Pharma Compliance Seminar 2015
© Copyright Ludwig Huber - LabCompliance Slide 2
Overview
• FDA Inspections and reports
• GMP compliance along the sample and data workflow
• Recent FDA warning letters & 483s and recommendations
how to avoid FDA warning letters related to
– Requirements for quality systems
– Requirements applicable for every workflow step
– Requirements applicable for individual workflow steps
• Responding to Warning Letters and 483’s
• Preparing the laboratory for FDA and equivalent
international GMP inspections
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© Copyright Ludwig Huber - LabCompliance Slide 3
FDA Inspection Documentation
• 483 Form Inspection Observation
– only deviations listed
– written for inspection exit meeting
• Establishment Inspection Report (EIR)
– very detailed (20-40 pages)
– more like an inspection protocol
• Warning letter
– With significant deviations
– Reviewed by FDA centers
For examples, please check: www.fdawarningletter.com
© Copyright Ludwig Huber - LabCompliance Slide 4
483 Form Inspection Observations
• Written during or after the inspection
• Discussed with and handed out to the user firm in the inspection exit meeting
• May reflects the view of the inspection team
• Major problem: inconsistency
• Available to the public, including to competition, through FOI (Freedom of information)
• Can have negative impact on company’s reputation
• Can have other consequences: withholding product approvals
• Companies are advised to respond within 15 days
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Establishment Inspection Reports (EIR)
• Written when the inspector is back in the office
• Very detailed inspection protocol, e.g., lists
question/answers and positive and negative
findings
• Reviewed by regional headquarter office
• Helpful in preparation for FDA inspections
• Available through FOI and private service providers
(e.g., some are listed on
www.fdawarningletter.com)
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Warning Letters
• Issued in case of severe deviations
• Reviewed by higher level FDA officials
• Frequently make reference to 483 inspection observations and to company responses
• Companies are advised to respond within 15 days
• Typically follow inspection scheduled
• The FDA publishes warning letters on two websites– http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/
– http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/default.htm
www.fdawarningletter.com
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What about Europe
• EMA launched new version of the EudraGMDP
website
• Incudes statements of non-compliance with GMP and
positive GMP certificates
• Information includes company name, location, issue
date, nature of no-compliance and the action taken
by issuing authority in order to protect public health
• Examples for actions taken
– Withdrawal of current valid GMP certificate
number
– Batch recallhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2
013/12/news_detail_001994.jsp&mid=WC0b01ac058004d5c1#press-release
© Copyright Ludwig Huber - LabCompliance Slide 8
Example from EudraGMDP Website
Nature of non-compliance : 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.
Issue Date
March 21
2014
Company and location
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© Copyright Ludwig Huber - LabCompliance
Consequences of Non-Compliance
• FDA Press release on Jan 25, 2012
• Prevents temporary import for products from two sites in India
• Causes pay cut for company executives and directors
• Ranbaxy to hire consultant with expertise in data integrity
• Possible delay of generic versions of blockbuster drugs (e.g.
Lipitor) with uncalculatabled costs
30 products were banned
from the US market
• GMP violations
• Inadequate testing
• Falsified data
• Data integrity issues
Slide 9
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Typical Warning Letter Statement
• Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations.
• Include an explanation of each step taken to prevent the recurrence of violations and copies of supporting documentation.
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© Copyright Ludwig Huber - LabCompliance Slide 11
Responding to Deviation Findings
• During the inspection before the inspection
observation has been drafted
• In response to the 483 inspection
observations
– Not legally required but recommended to
reply within 15 days
• In response to warning letters
– Legally required: 15 days
• Through other communications with the FDA
© Copyright Ludwig Huber - LabCompliance Slide 12
Missing Roles and Responsibilities
Reference: www.fdawarningletter.com (242)
• Deviation
Data security protocols are not established that describe the user's
roles and responsibilities in terms of privileges to access, change,
modify, create, and delete projects and data (242)
• Root Cause (assumed)
The company was not aware that user roles and privileges need to be
defined
• Corrective actions
- Develop procedure to define access levels and user rights
- Upgrade the system with suitable software-
- Implement the procedure for the inspected system
• Preventive actions
Implement the procedure on all regulated computer systems
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Compliance across the GMP Lab
SamplingSample
handlingTesting Test reports
Record
maintenance
Sampling plan &
representative
sampling, statistics
reserve samples
Sample
identification &
protection of
sample integrity
Monitoring the
quality of test
results, generate
complete records
Test conditions
& test results, data
review, handling
OOS & OOT
Ensure
record
integrity &
security
GMP controls across all workflow steps
• Validation of analytical
methods & procedures
• Equipment calibration
testing & maintenance
• Qualification of material
• Traceability
• Handling Out-of-specification
results
• Qualification of personnel
• Controlled environmental
conditions
• Written procedures
Quality system controls across the laboratory
Documentation control, corrective & preventive actions, complaint handling,
supplier & subcontractor management, internal audits, change management,
management reviews, continuous improvement, product reviews
Slide 13
Trace forwardTrace backward
Slide 13
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Poor Quality System • It is apparent that you have not implemented
a robust quality system at your firm.
• Be advised that corporate management is responsible
for ensuring the quality, safety, and integrity of drugs
• FDA strongly recommends that your corporate
management immediately undertake a comprehensive
evaluation of global manufacturing operations to ensure
compliance with CGMP regulations (W-287)
Corporate initiates implementing a global quality system
using ICH Q10 “Pharmaceutical Quality Systems” as a
guidance.
Make sure that the quality system is understood,
implemented and maintained
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© Copyright Ludwig Huber - LabCompliance Slide 15
Responsibilities not Defined
• The document control SOP lists “quality manager” and “technical manager” under “Responsibility” for document control, but does not clarify the individual roles of each. (W-247)
• Failure to have a document, which delineates the responsibilities and procedures applicable to the quality control unit (W-044)
Define written roles and responsibilities for each
person and function in quality assurance, quality
control and for technical management
© Copyright Ludwig Huber - LabCompliance Slide 16
Inadequate Document Control
• Your firm failed to establish and maintain adequate procedures to control documents and ensure all obsolete documents are promptly removed from use or otherwise prevented from unintended use (W-212)
Describe how written documents are initiated,
authored, reviewed, approved distributed and regularly
reviewed and updated
Describe how staff is trained on new and updated
procedures and how obsolete procedures are removed
www.fdawarningletter.com
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SOPs not Followed
• Failure to establish control procedures designed to assure batch uniformity and the integrity of drug products (W-066)
• Operations and QC personnel failed to follow procedures in the conduct of the last three GC Calibrations (W-240)
Verify through internal audits that written procedures are
Available for all critical routine tasks
Accurate (compliant with GMP)
Understood
Followed
© Copyright Ludwig Huber - LabCompliance
No on-going GMP Training
• Our review of your firm's training program disclosed that
there was no requirement for on-going CGMP training of
employees.
• The firm only had an initial CGMP training and did not
provide regular CGMP training to all employees involved
in the manufacture of drug products.
• There is no reference to CGMP training of supervisors or
directors. (W-219)
Include in the training program a schedule for regular
cGMP training
Make sure everybody working under GMP attends all GMP
trainings, including supervisors and directors, and IT
personnel
Slide 18
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© Copyright Ludwig Huber - LabCompliance
No Supplier Quality Agreement
• Failure to establish and maintain the requirements, including
quality requirements that must be met by suppliers.
• For example, your firm has not specified quality requirements
for suppliers, maintained lists of approved suppliers and
developed written procedures describing how suppliers are
evaluated for quality acceptance requirements (W-048).
Develop an SOP for assessment of material suppliers
Include a list with quality requirements
Develop and maintain a list of approved suppliers
Slide 19
© Copyright Ludwig Huber - LabCompliance
No Qualification of Material
• There is no assurance that your firm establishes
the reliability of the supplier's analyses through
appropriate validation of the supplier’s test results
at appropriate intervals (W-245)
• There are no incoming component specifications for
acceptance and no supplier quality agreements
(W-254)
www.fdawarningletter.com
Develop a procedure to ensure the quality of incoming
material through
Testing of the incoming material or
Supplier assessment and agreements
A combination of the above
Slide 20
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© Copyright Ludwig Huber - LabCompliance
Contract Laboratories not Qualified• Your firm did not qualify the contract laboratories used for
the testing.
It is FDA's expectation that your firm have a quality
agreement with the contract laboratories in place.
We recommend that this agreement be signed by all parties
involved and that it include, as a minimum, specific details
delineating the roles and responsibilities of each party
And a description of the materials, services,
communication, and all testing expected to be performed
by each party should also be included. (W-219).
Slide 21
Assess conformity to the agreement through audits
© Copyright Ludwig Huber - LabCompliance
No Documentation of Chemicals, Reagents, Solutions
• During the laboratory walkthrough, several solutions were
observed inside the refrigerator, with precipitation, that
apparently are uses for system suitability testing with no
indication of preparation date, lot number, and expiry
dates (W-241)
Develop a procedure to document material, e.g.,
chemicals, reagents, solutions and standards indicating the
Preparation date
Expirations date
Lot number
Storage conditions (temperature, humidity, light)
Slide 22
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Method Validation
• The accuracy, sensitivity, specificity, and reproducibility of test methods have not been established and documented (W-187)
The FDA frequently mentions these four parameters as the
only required validation parameters, They are listed in CFR
211 but not sufficient. You need to do more
Study ICH Q2 and USP 1225 and develop an SOP
accordingly
Start looking at the new FDA Method Validation guidance
from 2014, It has modern elements as Quality by Design,
Design of Experiments, and integrated lifecycle
management
© Copyright Ludwig Huber - LabCompliance Slide 24
No Forced Degradation for Stability Indicating Methods
• During the inspection your firm could not provide forced degradation data to support suitability of the HPLC test method for stability testing (W-274)
Proof the suitability of the testing method for stability
testing through the use of forced degaradation samples
When transferring stability indication methods between
laboratories proof the suitability of the receiving
laboratory through succesful testing of degradation
products .
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Compendial Methods not Verified
• Method verifications for compendial tests are not performed. Any method, including compendial methods, must be verified as suitable under actual conditions of use (W-274). .
Demonstrate that your laboratory is suitable to run
compendial methods under actual conditions of use
Follow USP general chapter <1226> as a guideline for
verification of compendial methods
Repeat one to three validation experiments
Using the risk based approach select validation studies
that are most difficult to pass.
© Copyright Ludwig Huber - LabCompliance Slide 26
No Formal Method Transfer• The firm failed to determine the acceptability of ten
methods prior to using them in the QC laboratory through formal method transfer procedures (282)
• Methods that were validated at one facility and transferred to xxx site are being used without a methods transfer or revalidation protocol. (W-186)
• Demonstrate that the receiving laboratory is suitable to
run the method under actual conditions of use
Follow USP general chapter <1224> as a guideline for
transfer of analytical method
Unless there is any specific reason not to do so, use
the comparative testing approach for the transfer .
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© Copyright Ludwig Huber - LabCompliance Slide 27
No Equipment Qualification Program
• The calibration procedure for HPLC systems is inadequate in that it did not include the detector’s linearity, injector’s reproducibility, and accuracy of temperature settings for the column heater (W-097)
• Failure to have an adequate qualification (calibration) program for the QC laboratory instruments.(W-246)
Use the USP <1058> approach for analytical
equipment qualification and calibration.
Use the equipment supplier‘s test procedures and/or
qualification services to ensure FDA compliant testing
© Copyright Ludwig Huber - LabCompliance Slide 28
Equipment Qualification Raw Data Missing
• You were unable to provide raw data or documentation regarding the qualification and calibration of your instruments and data to demonstrate that your quality unit reviewed and approved the work performed by your contractor. (w-246)
Make sure that the qualification records are complete
Develop an SOP that defines what constitutes a
complete record for each qualified instrument.
Examples are (electronic) raw data, supporting material
such as chromatograms and spectra, signatures of the
engineer who performed the qualification and the
signature of a reviewer.
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© Copyright Ludwig Huber - LabCompliance Slide 29
Equipment Failures not Investigated
• Deviations pertaining to laboratory equipment failures were not investigated. During the review of the service report log books for HPLC and GC units, the investigator found many instances of servicing due to instrument problems that were not documented as deviations(W-287).
Record and Investigate any equipment malfunction that
may have an impact on quality control testing
Investigation should include an evaluation if the quality
of test results, generated at or before the malfunction,
could have been impacted..
© Copyright Ludwig Huber - LabCompliance Slide 30
No Failure Investigations for failed Calibrations
• There was no documentation that an investigation was conducted to determine the root cause of the failed calibrations of the Gas Chromatograph.
• In addition, your firm failed to implement adequate corrective action to prevent re-occurrence..(W-240)
In case of failed equipment calibration
identify the root cause why this happened
develop and implement a corrective action plan
develop and implement preventive action plan
verify the corrective and preventive action plans for
effectiveness
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© Copyright Ludwig Huber - LabCompliance Slide 31
No Measures for Equipment Performance Qualification
• The HPLC performance qualification lacks sample energy (intensity of light source), and lamp use hours determination. (W-246)
Establish a performance qualification program to ensure that
the equipment runs on a day-by-day basis without any
problem
Put controls into the system that measures the performance
of critical parts such as the lamp which has a direct impact
on the limit of detection and limit of quantitation.
The lamp usage time is one possibility but measurement of the
on-going lamp energy or the HPLC baseline noise is more
meaningful.
© Copyright Ludwig Huber - LabCompliance
No Computer Validation at the Users Site
• During the inspection, I asked if the computer software has been
validation to assure that it performs for it's intended use.
• I was told that the software was validated by the manufacturer.
The managing director provided me a copy of the letter the
received from (the vendor).
• The letter indicated that the software was validated. She also
gave me a copy of validation information that was obtained from
(the vendor) during the inspection. (W-191)
I told the managing director I still need to see what
they have done to validate the system since the
computer was making a decision to accept or reject
potential donors
Slide 32
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© Copyright Ludwig Huber - LabCompliance
Excel Spreadsheets not Validated and Controlled
• The calculation for residual solvent uses an Excel
spreadsheet that has not been qualified. We are concerned
about the data generated by your QC laboratory from non-
qualified and uncontrolled spreadsheets
• The use of the Excel® spreadsheets in analytical calculations
are neither controlled nor protected from modifications or
deletion (W-286)
Develop an SOP: “Validation and Control of Spreadsheet
Application with recommendations for
Validation using the lifecycle approach (DQ/IQ/OQ/PQ)
Control focusing on security and integrity of records
and spreadsheets
Slide 33
© Copyright Ludwig Huber - LabCompliance
No Statistical Rational for Representative Sampling
• Your rationale for inspection of reserve samples is not based
on acceptable statistical sound assessment (W- 266)
• Failure to collect a sufficient number of samples based on a
validated statistical plan. (W-186)
• Samples taken of drug products are not representative and
properly identified. (W-266)
• Please provide scientific rationale for your current sampling
procedure and any revised SOPs with supportive documents.
(W-245)
Develop valid statistical controls, e.g., for
Sampling plans for drug products and for
Visual inspections of reserve samples
Slide 34
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© Copyright Ludwig Huber - LabCompliance
Inadequate System Suitability Testing
• Methods do not include system suitability tests to ensure that
the system is operating properly (W-162)
• No System Suitability performance before running testing (132)
• The SOP requirement for the assay analysis of xxx was not
followed in that the HPLC system suitability test was only
performed weekly per firm SOP, instead of the actual time of
testing (W-133)
Develop a procedure for system suitability testing
What needs to be tested – check USP chapter 621
When should the test be done – what frequency
Make sure the SOP is followed
Slide 35
© Copyright Ludwig Huber - LabCompliance
Trial Sample Injections not Recorded
• Our investigators identified your practice of performing trial
sample injections for HPLC analyses.
• For example, trial injections of stability samples were
acquired in the “Test” folder prior to official testing.
Immediately after the trial injections were completed, the
official samples were analyzed.
• The trial injection raw data, captured in the back-up files,
were deleted from the test folder. (W-295)
Develop a procedure to determine instrument readiness
Equilibrate the complete system without sample
injections, but under real HPLC conditions
Run system suitability test runs
Store all data in a sample folder and review the data
Slide 36
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© Copyright Ludwig Huber - LabCompliance
Selective System Suitability Test Results discarded
• Your analyst selectively invalidated data during related
substance testing. For example, for (b)(4), batch (b)(4) on May
15, 2013; you did not retain data from all six injections used
for the initial system suitability. Your analyst discarded one of
the six injections performed with no justification. (W-294)
Develop a procedure for system suitability testing
Follow USP 621 for conducting the tests
Ensure that all SST runs are recorded
Investigate failed runs
Stop sample analysis after failed runs
Slide 37
© Copyright Ludwig Huber - LabCompliance Slide 38
No Procedure for Chromatographic Peak Integration and Re-integration• The inspector documented that HPLC processing methods
(including integration parameters) and re-integrations are
executed without a pre-defined, scientifically valid procedure
• A QC operator interviewed during the inspection stated that
integrations are performed and re-performed until the
chromatographic peaks are “good”, but was unable to
provide an explanation for the manner in which integration is
performed.. (W-287)
Optimize chromatography to avoid re-integration
Develop a prodecure for integration and re-integration
Define when special authorization is required
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© Copyright Ludwig Huber - LabCompliance Slide 39
No SOP and Inadequate Handling of Out-of-Trend Results
• There is no standard operating procedure in
place that describes the steps to be followed during
an Out-of-Trend (OOT) Investigation
• Besides, the "OOT Investigation"
performed was inadequate. (W-241)
1. Study requirements for handling OOT results
2. Develop an SOP for FDA compliant handling OOT
results
© Copyright Ludwig Huber - LabCompliance
Incomplete Laboratory Test Records • Laboratory records do not include the initials or
signature of a second person showing that the original
records have been reviewed for accuracy, completeness
and compliance with established standards. (W-241)
Make sure that the laboratory test records are complete
Develop an SOP that defines what constitutes a complete
test record, check 21 CFR 211.194(a)
Examples are (electronic) raw data, supporting material
such as chromatograms and spectra, signatures of the
analyst who performed the test and the signature of a
reviewer.
The reviewer checks if all ‚required records‘ are available
Slide 40
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© Copyright Ludwig Huber - LabCompliance Slide 41
Incomplete Raw Data
• Your Quality Unit failed to provide all spectra and raw data associated to the reports. (W-248)
• The laboratory records do not include raw data to support the evidence of sample preparation, standards preparation and did not include a statement of the weight or measure of the samples used for each test (W-248)
Make sure that the laboratory raw data are complete
either in paper or in electronic form
Develop an SOP that defines what constitute complete
raw data, check 21 CFR 211.194(a)
For examples see above
© Copyright Ludwig Huber - LabCompliance
Electronic Raw Data not Saved
• Operating parameters of the spectroscopy system were
maintained with the relevant test records. However,
electronic raw data was not saved (W-167).
21 CFR Part 211: (e) requires that complete records shall be
maintained of all stability testing performed in accordance
with Sec. 211.194 (e)..
Develop a policy and procedure that for HPLC data
electronic records must be saved and available for
inspectors
Slide 42
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© Copyright Ludwig Huber - LabCompliance Slide 43
Missing Audit Trail
• Data stored on the computer can be deleted, removed,
transferred, renamed or altered (W-209)
• There is no audit trail or log of data changes that are
made to the information in the database. (W-224)
Develop procedural and technical controls to ensure
electronic audit trail
Include audit trail in the URS
Make sure that the audit trail function can not be
switched off by the operator
Validate audit trail function
© Copyright Ludwig Huber - LabCompliance
Electronic Audit Trail not Reviewed
• Your firm's review of laboratory data does not include a
review of an audit trail or revision history to determine if
unapproved changes have been made.. (W-229)
Develop a procedure for reviewing electronic audit trail
Inform you laboratory staff that audit trails are
reviewed
Include audit trail review as checklist item in regular
data review and approval
Ask software suppliers to handle creation and review
of audit trail tables more user friendly
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© Copyright Ludwig Huber - LabCompliance
Manipulation of Printed Raw Data
• Your firm's laboratory analyst had modified printed raw
data related to the IR Spectra test
• Your quality control unit failed to detect that IR spectra
were being substituted by a laboratory employee and detect
the manipulation or alteration of laboratory documents
Use internal or external data integrity specialists
to review and aprove critical records
The specialists should also look at historical data
Slide 45
We highly recommend that you hire a third party
auditor, with experience in detecting data integrity
problems (W-230)
© Copyright Ludwig Huber - LabCompliance Slide 46
Summary GMP Issues Related to Laboratories• Written procedures (SOPs)
• Supplier assessment
• Material qualification
• OOS/failure investigations
• Equipment qualification
• Method validation
• System suitability testing
• Review of data
• Archiving of data
• Data integrity and security
• Personnel – Training
www.fdawarningletter.com
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© Copyright Ludwig Huber - LabCompliance Slide 47
Responding to Inspection Deviations
• Fully understand the content of each deviation in the exit meeting
• Respond in time (15 days for FDA Warning Letters and 483s)
• Address each item separately in the response
• Start with a statement that you understand and accept the deviation
• If some deviations are already fixed, provide documented evidence
• For others write how you will correct the deviation: Who, how, when
• Attach preliminary documentation for the corrections, if available
• Commit to train all affected personnel
• Write how you will prevent the same of similar problem re-occurring
(preventive action)
• Write how to evaliate and follow-up on past shipments (historical
data)
© Copyright Ludwig Huber - LabCompliance Slide 48
Global Response to the same and similar deficiencies
• Although your corrective actions may adequately
address the protection of the (b)(4) computer
from non-traceable changes, your firm has not
taken a global approach to this deficiency. It is
our expectation that your other manufacturing
and laboratory computerized systems will be
reviewed to ensure similar deficiencies do
not exist (FDA WL-253).
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© Copyright Ludwig Huber - LabCompliance Slide 49
‘Inspection’ Like Internal Audits
• Opening meeting with management• Review last audit and corrective actions• Review organizational structure, tasks and
responsibilities• High level documentation, e.g., quality plan• Review selected procedures• Review selected records• Walk through the operation• Observe and interview people at work• Exit meeting with management• Follow-up activities
© Copyright Ludwig Huber - LabCompliance
Resources• Agilent Primers
– Analytical Instrument Qualification and System Validation
– Validation of Analytical Methods
– Good Laboratory Practice and Good Manufacturing Practice
– Understanding and Implementing ISO/IEC 17025
– Compliance for BioPharmaceutical Laboratories
– Qualification and Validation for Supercritical Fluid Chromatography
– Elemental Impurity Analysis in Regulated Pharmaceutical Laboratories
– Compliance by Design“ for Quality Control Laboratories:
Learning from FDA Warning Letters
Other Resources
– Tutorials (method validation, computer validation, GLP)
– References to FDA Warning letters and 483s
– Free Labcompliance Newsletter
www.labcompliance.com/agilent
(available until September 30, 2015)
Slide 50
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© Copyright Ludwig Huber - LabCompliance
Thank You
I would like to thank
• All attendees for your attention
• Agilent Technologies for invitation and organization
Slide
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