Transcript Slide 1

FDA/EU Compliance for Quality Control
Laboratories
Ludwig Huber, Ph.D
Chief Advisor, Global FDA Compliance
Ludwig Huber
Phone: +49 7902 980582
E-mail:
[email protected]
Page 1
Overview
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Planning for GMP compliance
Develop procedure and other documents
Building the right laboratory organization
Qualify personnel and document qualification
Qualify suppliers and materials
Validate analytical methods
Calibrate and qualify equipment and computer
systems
• Implement procedures for sampling and sample
analysis
• Implement procedures for data review, approval
and archiving
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Ludwig Huber - LabCompliance
Slide 2
GMP and ISO 17025 Laboratory Compliance
Sampling
Representative
Sampling
Sampling plan
Sample
handling&
storage
Data review
and
approval
Testing
Avoid cross
Contamination
Ensure sample
integrity
Clear
specifications
& test
protocols
Record
archiving
Primary &
Ensure data
secondary
Integrity @
review
availability
Handling OOS
Compliance across all workflow steps
• Validation of analytical • Qualification of material
methods & procedures • Traceability
• Equipment calibration • Control of nontesting & maintenance
conforming testing
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Ludwig Huber - LabCompliance
• Qualification of personnel
• Controlled environmental
conditions
• Written procedures
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Plan for GMP/ISO 17025 Compliance
Compliance master plan / Quality Plan
• Guideline for effective and consistent
implementation of GMP regulation
• Documents the laboratory’s approach for
compliance
• Ensures efficiency AND consistency
• Useful for audits to explain the laboratory’s
approach towards compliance
Project Plan
• Outlines steps, tasks, deliverables and
owners
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Slide 4
Contents of the
Master/Quality Plan
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Policy
Quality management documentation
Organization and responsibilities
Staffing and people qualification
Selection and validation of analytical methods
Equipment and computers
Sampling and sample handling
Reagents and calibration standards
Testing
Handling non-conformance
Reporting and archiving
Ludwig Huber - LabCompliance
or
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Develop Procedures and other Documents
Policy
Master
Plan
High level, strategic documentation
(regulations, business, quality)
Training
Maintenance
Validation, Audits
Test procedures
Operation manuals,
QC procedures
Process related
documentation, approaches
(SOPs)
Product/event related documentation
(work instructions, also called SOPs
or test scripts, protocols)
Product test records, batch
records, validation results,
training records, chromatograms
Compliance Records
(batch/event related
documentation)
Use the same set throughout the
organization
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Slide 6
Build the Right Organizational Structure
and Assign Tasks (Example)
Director
Finance
& Admin.
Human
Resources
Lab 1
Laboratory
Mgmt.
Quality
Assurance
Lab 2
IT/IS
Safety
Officer
Lab 3
Avoid Conflicts of Interest
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Slide 7
Qualify Personnel
Job description
1. Define requirements
- what is the assigned task?
2. Identify knowledge
3. Determine gaps
4. Make a plan to fill the gaps
5. Train
6. Evaluate training
7. Document
1/2 year or yearly reviews
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Slide 8
Documenting Training
Job description
Trainings
Qualification
requirements
Supervisor
(name,
signature)
Name
Type,
content
Education
Experience
Date
Duration
Gaps, Trainings plan
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This documentation should be kept separated from other personnel
files, for example performance evaluations
Ludwig Huber - LabCompliance
Slide 9
Qualify Suppliers and Materials
1. Documenting internal and external experience
2. Mail audit with follow up
3. Direct audit
Criteria
• Product risk
• Supplier risk
#3. is most time consuming and
recommended for high volume and high
risk suppliers
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Slide 10
Incoming Quality Control of Material
• Purchase from qualified suppliers
• Limited sample testing
• Number of tests depend on
– Criticality of reference material
– Experience with the supplier
– Experience with initial tests
• Retest after specified time period (e.g., after one
year)
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Slide 11
Preparation of Working Standards
Primary Standard
Certified Reference
Material
Secondary
Standard
Company Internal
Reference Material
Working Standard
Method Validation
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Equipment
Calibration
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System
Performance Check
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Validate Analytical Methods
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Definition Method Scope
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Define Validation Criteria
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Test
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Define Routine Tests
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Sample matrix
Compounds
Equipment, Location
Optimize method parameters
Define performance
characteristics
Acceptance criteria
Develop test cases
Preliminary tests
Final tests
SOPs
System Suitability tests
Analytical quality control
Ludwig Huber - LabCompliance
Slide 13
Method Parameters and Tests
Parameter
Accuracy
Tests (examples)
Minimum at 3 concentrations, 3 replicates
Precision
Repeatability
Intermediate
Reproducibility
Specificity
Minimum of 9 determinations over the specified range
Over 3 days, 2 operators, 2 instruments,
Only required if testing is done in different laboratories
Prove with specific methods: HPLC, DAD, MS, dif. columns
Limit of detection
Limit of Quantitation
Visual approach, S/N >= 3
S/N >= 10, Standard deviation of response
Linearity
Min 5 concentrations: visual, correlation coefficient (r)
Range
80 to 120% of test concentration, from linearity tests
Well Characterized Biological Products
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Slide 14
Intermediate Precision Example
Sample
Day
Operator
Instrument
100% conc. (3x)
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1
1
100% conc. (3x)
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2
2
100% conc. (3x)
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3
3
100% conc. (3x)
2
1
2
100% conc. (3x)
2
2
3
100% conc. (3x)
2
3
1
100% conc. (3x)
3
1
3
100% conc. (3x)
3
2
1
100% conc. (3x)
3
3
2
• Minimum: 2 days, 2 operators, 2 instruments,
• Calculate overall RSD
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Slide 15
Examples for Acceptance Criteria
Quantitative Impurities in Finished Drugs
Parameter
Accuracy
Test
90 – 110%, 80 – 120% at specifications limit
Precision
Repeatability
Intermediate
Reproducibility
Specificity
Limit of Detection
Limit of Quantitation
Linearity
Range
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<1.5 % RSD (up to 15% at LOQ)
<2.0 % RSD (higher at LOQ)
< 3% RSD (higher at LOQ)
Peak resolution >1.5 (related substances)
or >2 (main peak)
Peak purity check with UV DAD or MS
N/A
0.05%
visual inspection of linearity curve, r>0.9900
o.k. if accuracy, precision, linearity criteria are met
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Slide 16
Example: Report Summary Table
Validation
Parameter
Accuracy
Method
Precision
Intermediate
Precision
Specificity
Linearity
Range
Robustness
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Measure
Acceptance criteria
Results
Recovery – Conc1
97 – 103 %
99%
Recovery – Conc2
97 – 103 %
100%
Recovery – Conc3
97 – 103 %
100%
RSD
≤ 1.5 %
0.4%
RSD
≤ 2.0 %
0.8%
Peak Resolution Factor R
R for all peaks >1.5
All peaks >2.0
Correlation Coefficient
≥ 0.9900
0.9900
Visual inspection of plot
Linear response plot
Shows linearity
Correlation Coefficient
≥ 0.9900
0.9900
Precision at 3 concentrations
≤ 1.5 %
<1%
Recovery at 3 Conc.
97 – 103%
99.6%
Column Temp. ±2 C
R for all peaks >1.5
R for all peaks >2.0
Mobile Phase ±2 %
R for all peaks >1.5
R for all l peaks >2.0
Sample extraction time -20 %
Recovery in spec.
Recovery in spec
Compound stability 6 days
<3% degradation
<2% degradation
Ludwig Huber - LabCompliance
Slide 17
Maintain, Calibrate and Qualify
Equipment and Computers
• Develop procedures for equipment purchasing, qualification,
calibration and maintenance
• Qualify the equipment
• Identify defect or non-qualified equipment
• Develop and implement maintenance and qualification
schedule
• Keep equipment under change control and re-qualify, if
necessary
• Record changes
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Slide 18
Equipment Qualification - 4Q Model
Design Qualification
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Installation Qualification
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Operational Qualification
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Performance Qualification
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User requirement specifications
Functional specifications
Operational specifications
Vendor qualification
Check arrival as purchased
Check proper installation of
hardware and software
Test of operational functions
Performance testing
Test of security functions
Test for specified application
Preventive maintenance
On-going performance tests
Ludwig Huber - LabCompliance
Slide 19
OQ Test - Example
Instrument
BestBalance
Serial number
55236A
Maximal weight
11 g
Control weight 1
10,000 mg
Limit +-10 mg
Control weight 2
1,000 mg
Limit: +-1 mg
Control weight 3
100 mg
Limit: +- 0.1 mg
Date
Weight 1 Weight 2 Weight 3
2/3/06 9999.8
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999.9
100.0
o.k.
Test engineer
Name
Signature
yes Hughes
Ludwig Huber - LabCompliance
Slide 20
Why Companies in EU/US Choose
Manufacturers Operational Qualification
Services
Tools
• Some tests require traceable test tools
• The tools typically need to be calibrated yearly
Qualification
• Test engineers must be formally qualified
• Training must be regularly updated and thoroughly documented
• Manufacturer engineer bring qualification certificates along
• Manufacturer engineers can fix problems if OQ does not pass
Documentation
• Vendors provide inspection ready documentation
Compliance
• There are many FDA warning letters based on user’s OQ
• I am not aware of a vendor’s OQ based warning letter
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Slide 21
Documentation of On-going PQ Testing
System Suitability Testing. Day-by-Day
Test #
Date
mm/
day
Time
a=am
p=pm
T10
T11
T12
T13
T14
Bl
noise
Tailing
factor
Peak
resol
Precis.
#1
Precis.
#2
Accept
Limit
>2.0
Accept
Limit
<1%
Accept
Limit
<1%
Accept Accept
Limit
Limit
<1x10-4 <1.3
Test
#
Date
Time
T10
T11
001
08/04
06.20 p
4.5x10-5 1.1
Comment
Passed/
failed
T12
T13
T14
Comment
2.3
0.61
0.50
passed
002
003
004
Example: HPLC System
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Slide 22
Computer System Validation Phases
Design Qualification
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Configuration
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Installation Qualification
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Operational Qualification
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Performance Qualification
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User requirement specifications
Functional/config. specifications
Vendor qualification
Configuration design
Configuration implementation
Check arrival as purchased
Check proper installation of
hardware and software
Test of configuration specifications
Test of functional specifications
Test of security functions
Test for user requirement
specifications
Preventive maintenance
Ludwig Huber - LabCompliance
Slide 23
Implement Procedures for Sample
Analysis
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Sampling
Sample handling
Testing
Data review and approval
Sampling
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Sample
handling&
storage
Testing
Ludwig Huber - LabCompliance
Data review
and
approval
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Sampling
• Sampling process well planned, executed according
to the plan and documented in the sampling
protocol
• Clean equipment to avoid
cross contamination
• Representative
• Sample location well defined
• Sampling should not change properties
• Should protect people taking the sample
Sampling
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Sample
handling&
storage
Testing
Ludwig Huber - LabCompliance
Data review
and
approval
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Reserve Samples (GMP only)
• Samples used for retesting of the
original sample if the initial test
results is non-conforming (out of
specifications) in the event of
customer complaints
• Typical amount: 1.5 x sample
amount
• Should be visually inspected for
deterioration at least once a year
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Slide 26
Sample Testing
• Develop test program for APIs, finished drugs,
raw material
• Develop clear specifications
• Document acceptance criteria and actual results
• Document test procedures and test equipment
• Formally review and approve test results
– Analysts
– Second person (technical & independent reviewer)
• Document test conditions with test results
Sampling
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Sample
handling&
storage
Testing
Ludwig Huber - LabCompliance
Data review
and
approval
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Review and Approval of Test Results
• Develop and follow procedure for review
of test results
• Review by the analyst: what to look
at, how to document
• Review and approval by a second person
• Release of test results
Sampling
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Sample
handling&
storage
Testing
Ludwig Huber - LabCompliance
Data review
and
approval
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Handling Failure Investigations /
Out-of-Specification Test Results
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Investigation required if a test result is out of specification
Required to identify the root cause of a problem
Should follow documented procedure
Failure can be caused by individual testing, process
error, or product problem
• Maintain a list of all OOS test results
• Corrective and Preventive Action Plans, Root Cause
Analysis
Follow FDA Guide: Investigating out of
Specifications Test Results for Pharmaceutical
Production
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Slide 29
Tasks and Responsibilities of the Analyst
• Perform test correctly
- be aware of potential problems
- follow SOPs
- follow good science
• Stop testing in case of OOS results
• Inform supervisor about OOS results
• Retain test preparations
- until data is reviewed and
investigation is finished
• Conducts and documents OOS, each step of
laboratory failure investigations and
investigation results
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Slide 30
(e)-Records Maintenance and Archiving
• Study regulations: which records are required, for how
long should they be archived?
• Define raw data
• Ensure track-ability of final results to raw data
• Maintain integrity of data
• When using electronic records, follow Part 11
• Ensure that electronic audit trail is available, activated
and reviewed
• Develop a strategy and procedures for backup, archiving
and retrieval of data
Sampling
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Sample
handling&
storage
Testing
Data review
and
approval
Ludwig Huber - LabCompliance
Record
archiving
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Conduct Internal Laboratory Audits
• Should be part of any good quality
system
• Develop audit plan and schedule
• Develop and implement a
corrective and preventive action
plan
• Plan for follow up inspections
• Conduct audit like FDA inspections
• Develop table of contents for each
audit report
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Slide 32
Audit Documents for Internal
and External Inspections
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Organization charts
Standard Operating Procedures
Study protocol
Data storage worksheets
Notebooks: paper and/or electronic
Analytical raw data
Instrument qualification, calibration and
maintenance protocols
• Records on personnel qualification
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Slide 33
Prepare Your Organization for FDA and
other Inspections
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Develop SOP for FDA inspections
Develop Checklist
Train management and staff
Conduct ‘FDA inspection like’ internal
audits
Establish an audit response team
Review previous inspections and corrective
actions
Reserve and prepare meeting rooms
Ludwig Huber - LabCompliance
Slide 34
Raw Data (1996)
• Operating parameters were maintained with the
relevant xxx. However, electronic raw data was not
saved (W-167).
21 CFR Part 211: (e) Complete records shall be
maintained of all stability testing performed in
accordance with Sec. 211.194 (e).
Study regulation and check if the print-out has all records
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Slide 35
FDA Enforcement: Mio$ 500 Fine
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30 products were banned
from the US market
• GMP violations
• Inadequate testing
• Falsified data
• Data integrity issues
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
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Slide 36
Raw Data (May 2013)
• During an audit of the data submitted in support of
the xxx tablets, 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.
Study regulation and check if the print-out has all records
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Ludwig Huber - LabCompliance
Slide 37
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
– Genotoxic impurities in pharmaceutical products
• Free tutorials (method validation, computer validation, GLP)
www.labcompliance.com/tutorial
• Seminar reference material, e.g., ppt presentations
www.labcompliance.com/agilent
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(available until July 15, 2015
Ludwig Huber - LabCompliance
Slide 38
Thank your very much for your
attention.
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Ludwig Huber - LabCompliance
Page 39
Thank You
I would like to thank
•
All attendees for your attention
•
Agilent Technologies for invitation and organization
Give feedback and choose any two from over 150 documents
(value: $138) for free: SOPS and/or Validation examples.
GOTO:
www.labcompliance.com/misc/conferences/feedback.aspx
offer expires on July 15, 2013
Check topics and details of 100+ audio/video seminars
Audio: www.labcompliance.com/seminars/audio
Video: www.labcompliance.com/seminars/video
Slide 40
Ludwig Huber
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Ludwig Huber - LabCompliance
Appendix
Examples for FDA Warning
Letters related to
Laboratories and how to
avoid them
Reference: www.fdawarningletter.de
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Ludwig Huber - LabCompliance
Slide 41
Training
• Failure to adequately establish procedures for
identifying training needs and ensure all personnel
are trained to adequately perform their assigned
responsibilities and the training is documented (228)
• Your firm fails to document on the job training.(228)
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Your firm failed to list second shift quality personnel,
their positions, and to whom they report within the
corporate quality structure.(228)
1. Develop a training plan for each employee with
identification of training needs
2. Document all training activities including on the job
training
and training of shift workers
Ref: www.fdawarningletter.com (W-228)
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Slide 42
Supplier and Material Qualification
• 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)
1. Develop and implement a supplier assessment program
2. Regularly test incoming material
Ref: www.fdawarningletter.com (W-228)
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Slide 43
Method Validation
• The accuracy, sensitivity, specificity, and
reproducibility of test methods have not been
established and documented (W-187)
• Failure of your quality control unit/laboratory to
ensure your analytical methods used to evaluate
the stability of your APIs are validated to be
stability indicating. (W-243)
1. Develop procedure for validation of analytical methods
2. Follow ICH Q2 for selecting test parameters and
conditions
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Slide 44
Method Changes
• Failure to maintain complete records of any modification
of an established method employed in testing [21 CFR
§ 211.194(b)] (W-171)
• Specifically, the records of laboratory methods stored in
the xxx computer system do not include the identity of
the person initiating method changes. (W-171)
• Appropriate controls are not exercised over computers or
related systems to assure that changes in analytical
methods or other control records are instituted only
by authorized personnel. (W-171)
Develop SOP on how to authorize and document
changes to analytical methods
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Ludwig Huber - LabCompliance
Slide 45
Method Transfer
The analytical method have not been transferred
between the issued laboratory and the two chemists
currently working in the QC laboratory. (W-241)
• The methods have been transferred before the two
chemists were hired.
• There are no records which document training in the
two procedures. (W-241)
• Methods that were validated at one facility and
transferred to xxx site are being used without a
methods transfer or revalidation protocol. (W-186)
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Develop SOP for analytical method transfer.
Follow USP <1224>, Train analysts in the receiving lab
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Slide 46
Verification of Compendial Methods
Method verifications for compendial tests are not
performed. Any method, including compendial
methods, must be verified as suitable under actual
conditions of use. This has not been done for any
method provided by your clients. (W-247)
Develop procedures for verification of compendial
methods following USP <1226>
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Slide 47
FDA Warning Letter/483/EIR
• Your firm failed to conduct injector and detector performance
testing for the HPLC system (221)
• For example, no HPLC injector and detector testing for linearity,
accuracy, and precision were conducted, such as: 1) various
injection volumes and standard concentration testing; 2)
evaluation of detector for noise/drift; and 3) carryover
testing to evaluate response at low levels to determine the
detection of possible interferences that may affect peaks of
interest (221)
Test HPLC for all parameters as specified
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Slide 48
Equipment
• Lacks documentation of installation and operation
qualification of equipment (160)
• The Validation Master Plan does not contain an
operational qualification for xxx (164)
• There is no requirement for a Performance
Qualification protocol (164)
Perform IQ/OQ/PQ for Equipment
Ref: www.fdawarningletter.com
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Slide 49
FDA Warning Letters - Equipment
• Failure to have a complete calibration program for
the HPLCs in that the gradient accuracy and
detector linearity is not being verified (W-110)
• The equipment xxxx used to analyze the Caffeine
product was not calibrated prior to use. (W-019)
1. Learn about details of equipment qualification
2. Develop, implement and enforce procedures
for equipment calibration and qualification
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Slide 50
FDA Warning Letter/483/EIR
• There was no documentation that an investigation was
conducted to determine the root cause of the failed
calibrations of the Gas Chromatograph (GC)
• In addition, your firm failed to implement adequate corrective
action to prevent recurrence.“ (WL-240)
1. Investigate and document the root cause for failed
calibration and qualification
2. Develop a corrective action plan
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Slide 51
FDA Warning Letter/483/EIR
• The quality control unit failed to adequately train personnel to
perform their duties for Operation of the Gas Chromatograph,
and failed to follow procedures in the conduct of GC
Calibrations.
1. Train operators when conducting instrument
qualification and document the training
2. Request training certificate when done by equipment
suppliers
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Ludwig Huber - LabCompliance
Slide 52
FDA Warning Letter/483/EIR
• The calibration program for your stability chambers is
deficient ill that it does not include specific directions and
schedules.
• You do not perform re-qualification of the stability chambers.
1. Develop a program for equipment calibration and
calibration. Include a schedule
2. Conduct regular requalification of equipment
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Ludwig Huber - LabCompliance
Slide 53
FDA Warning Letter/483/EIR
• No IQ, OQ or PQ has been performed throughout
the life of the system. No validation reports have
been generated historically (for the legacy system).
• The (system) has not been maintained under
established procedures for change control. This is
true throughout the life of this software application.
(W-190)
Develop a procedure for validation and change control of
legacy system.
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Ludwig Huber - LabCompliance
Slide 54
FDA Warning Letter/483/EIR
• The validation results do not meet the pre-determined
acceptance criteria, and there was no documentation why the
results were acceptable. The validation reports do not
contain an evaluation of the validation data and activities. Nor
does it contain validation analyses and conclusion (W-204)
1. Develop a test plan. Part of it should be to define
test cases acceptance criteria a procedure in case
the criteria are not met.
2. During the review procedure, check if tests results
meet acceptance criteria
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Ludwig Huber - LabCompliance
Slide 55
FDA Warning Letter/483/EIR
• Appropriate controls are not exercised over computers or
related systems to assure that changes in master
production and control records or other records are
instituted only by authorized personnel (W-198).
• There were no written protocols to assign levels of
responsibilities for the system (W-209)
Authorize users for specific functions
Define user rights per procedure
Reference: www.fdawarningletter.com
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Slide 56
Sampling, Sample Handling
• Failure to retain reserve samples of each batch of each
API (W-173)
• Representative samples are not taken of each shipment
of each lot of components for testing or examination (W245)
• Certain elements of sample integrity are addressed in
other SOPs, but none of the procedures explicitly call for
maintaining sample integrity throughout the testing of
the sample. (W-247)
Develop sampling plan and SOP for sampling
Ensure representative sampling
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Ludwig Huber - LabCompliance
Slide 57
FDA Warning Letter/483/EIR
• "System suitability conducted for Dissolution Assay per
laboratory test methods evaluates only five replicate
injections for Relative Standard Deviation (RSD). For NMT
3%. USP requires six replicate injections for instrument
precision and accuracy“
1. Study USP requirements for System Suitability Testing
2. Develop , implement and audit tests
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Ludwig Huber - LabCompliance
Slide 58
Data Review
• 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)
• In addition, 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.. (W229)
Develop SOP for data review by analyst and
independent second person
Include review of electronic audit trail
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Ludwig Huber - LabCompliance
Slide 59
Data Manipulation
• Our investigators also found many instances with
extensive manipulation of data with no explanation
regarding why the manipulation was conducted.
• This manipulation would include changing integration
parameters or re-labeling peaks such that previously
resolved peaks would not be integrated and included in the
calculation for impurities (W-203)
Justify and document any data modification
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Ludwig Huber - LabCompliance
Slide 60
FDA Warning Letter/483/EIR
•
•
•
Data stored on the computer can be deleted, removed,
transferred, renamed or altered (W-209)
There should be a record of any data change made, the
previous entry, who made the change, and when the
change was made. (W-209)
No software changes in the study data could be
detected as there was no audit trail capability (W-185)
Record any changes to data in an audit trail
Reference: www.fdawarningletter.com
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Ludwig Huber - LabCompliance
FDA Warning Letter/483/EIR
• There are no procedures for backing-up data files and
no levels of security access established“ (W-138)
• You had not established an electronic data back-up
procedure (W-185)
Procedures and technical controls for secure back-up
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Ludwig Huber - LabCompliance
Slide 62
Data Archiving
• Records are issued from the record storage room
without any written checkout procedures, and
instead upon verbal direction by the QA manager.
(W-247)
• 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)
Develop procedure with responsibilities and
technical controls for data archiving
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Ludwig Huber - LabCompliance
Slide 63