Transcript Slide 1

FDA 483 and Warning Letter
Interpretation with real Case Studies
The Agilent Pharma Compliance and Validation
Seminar and Workshop
Dr. Ludwig Huber
[email protected]
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Regulatory Inspections
• Opening meeting with inspection team and laboratory
management
– Review last audit and corrective actions
– Agree on final agenda
• Investigate documentation in an office room
– Review organizational structure, tasks and
responsibilities
– High level documentation, e.g., quality plan
– Review selected procedures
– Review selected records
• Walk through the laboratory
– Observe and interview people at work
– Inspect one or more systems previously discussed
• Exit meeting with management
• Follow-up activities
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Inspection Documentation
• 483 Form Inspectional Observation
– only deviations listed
– shows the view of the inspection team
– written for and discussed during the 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
www.fdawarningletter.com
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Slide 3
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 (W-228)
• Your firm fails to document on the job training. (W-228)
• Your firm failed to list second shift quality personnel,
their positions, and to whom they report within the
corporate quality structure. (W-228)
www.fdawarningletter.com
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Slide 4
Supplier Assessment
• 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
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Slide 5
Equipment Qualification
• Failure to have an adequate performance qualification
(calibration) program for the QC laboratory instruments.
• Your HPLC calibration lacks a carry over test (sample
injection residual test), sample energy (intensity of light
source), and lamp use hours determination.
• You fail to challenge the analytical balances for minimum
weight, measurement for uncertainty, and drift value.
• In addition, you do not calibrate the Karl Fisher syringe
used during xxx API water content analysis.) (W-246)
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Slide 6
Method Validation and
Transfer
• 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)
• Methods that were validated at one facility and
transferred to xxx site are being used without a
methods transfer or revalidation protocol. (W186)
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System Suitability Testing
The suitability of all testing methods is not verified
under actual conditions of use.- The HPLC
configuration tubing at the time of method validation
may not be similar to actual ones used possibly
affecting the resolution. (W-241)
• 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 (133)
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www.fdawarningletter.com
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Slide 8
Incomplete Laboratory Records
• Failure to have laboratory records that include
complete data derived from all tests necessary to
assure compliance with established specifications
and standards.(W-214)
• Laboratory records fail to include the initials or
signature of the person who performs each
laboratory test [21 CFR § 211.194(a)(7)].
• Specifically, laboratory analysis records for analyses
performed on HPLC xxx and xxx do not indicate
which analyst performed the injections. (W-171)
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Slide 9
Consequences of non-Compliance
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483 form inspection reports
Warning letters
Shipment hold
Product recall
Seizure
Import alerts and denials
Consent decree
Debarment
(personnel excluded from certain positions)
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Slide 10
Consequences of Non-Compliance
30 products were banned
from the US market
• GMP violations
• Inadequate testing
• Falsified data
• Data integrity issues
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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 11
Responding to FDA Inspectional
Deviations
• 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
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Slide 12
Responding to FDA/CFDA Deviations
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Exit meeting: Fully understand the content of each deviation
Respond in time in writing (15 business days)
Address each item separately
Mention that you understand and accept the deviation
If some deviations are already fixed, provide documented
evidence
For others give a reason for the deviation, 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 reoccurring
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Slide 13
Prepare Your Organization for FDA
Inspections
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Design GMP compliance through learning
from warning letters
Develop SOP for FDA inspections
Develop Checklist
Train management and staff
Conduct ‘FDA inspection like’ internal audits
Learn how to effectively to respond
inspection reports
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Response to 483 too late
483 received on August 26, 2010
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We acknowledge your written response, dated September 23,
2010,, to the Form FDA 483.
However, because this responses were received more than 15
business days after the Form FDA 483 was issued; this response
have not been considered.
We plan to evaluate your additional responses to the Form FDA
483, along with any other written material provided, as a direct
response to this Warning Letter
www.fdawarningletter.com (253)
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Slide 15
Inadequate Response to 483
Deviation
• For example, the employees of your firm, including a member of
your quality control staff, admitted to our investigators that they were
unaware of and were not trained to follow your SOP for handling
deviations. There were at least two instances in which an OOS
investigation was not conducted.
Inadequate Response
• While your response proposes to provide training to all employees, it
does not provide documentation that you have initiated the training
and does not specify a timeframe for completion.
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In addition, your response fails to specifically address how the
proposed training will ensure that all employees will be trained in
SOPs that are relevant to their job functions..
www.fdawarningletter.com (253)
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Inadequate Response to 483
Deviation from inspection in Sept Oct 2010
• Failure to calibrate, in accordance with written procedures and an
established schedule, weighing equipment critical for ensuring the
quality of APIs.
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Inadequate Response
• In your response, your firm provided certification calibration records
from your calibration services contractor to address actual use ranges
of the balances.
• Your response, however, is inadequate because you do not include
any information regarding a calibration program to ensure future
calibration of balances on a routine basis.
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Slide 17
Deviation: HPLC for Testing of xx not
Qualified
Corrective Action
Preventive Actions
Details
How to
qualify?
Time
frame?
Training
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Qualify
that
specific
HPLC
Impact on
other
tested
products?
Other
HPLCs
in the
lab?
Other labs?
Global
Approach?
Other
Lab
Equipment?
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Responding to 483s/
Warning Letters
• Devitions
– 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 (W-228)
• Root cause (assumed):
– No document on how to handle training
• Suggestions for corrective action to correct the existing violation
– Develop and implement procedure on how to handle training, including
documentation, responsibilities, second shift worker
• Suggestions for preventive actions to prevent reoccurrence of the
same or similar problem at the same or similar location
– Develop a comprehensive training plan and SOPs that cover all
aspects of people qualification, including documentation and
assessment.
• Documentation: Corrective and preventive action plans with owners and
deliverables, time schedule
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Workshop Overview
1. Small groups of attendees review most frequently cited
FDA Warning letters/483’s related to laboratory
controls
2. Groups discuss and document
a. The root cause (reason for the problem, if it is not
obvious, make something up, but only one!!!)
b: Suggestions for corrective actions, must be in line
with the suggested root cause
c: Suggestions for prevention actions
d. Suggestions for documents to be provided to FDA
3. Groups present the outcome to the entire audience (In
english or Japanese)
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Slide 20
Free Resources
• Agilent Primers
– Analytical Instrument Qualification and System Validation (Chinese)
– 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
– „Quality 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, 2014
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Slide 21
Thank You
I would like to thank
• All attendees for your attention
• Agilent Technologies China for invitation and
organization
Check topics and details of 200+ audio/video seminars
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