1. FDA 483 and Warning Letter Interpretation with real Case Studies
The Agilent Pharma Compliance and Validation Seminar and Workshop
Dr. Ludwig Huber

2. Regulatory Inspections
4/22/2017
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

3. 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

4. Examples
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)

5. Examples 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)

6. Equipment Qualification
Examples
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)

7. Method Validation and Transfer
Examples
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. (W-186)

8. System Suitability Testing
Examples
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)

9. Incomplete Laboratory Records
Examples
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 § (a)(7)].
Specifically, laboratory analysis records for analyses performed on HPLC xxx and xxx do not indicate which analyst performed the injections. (W-171)

10. Consequences of non-Compliance
4/22/2017
Consequences of non-Compliance
483 form inspection reports
Warning letters
Shipment hold
Product recall
Seizure
Import alerts and denials
Consent decree
Debarment (personnel excluded from certain positions)

11. Consequences of Non-Compliance
4/22/2017
Consequences of Non-Compliance
500 M$ Fine
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

12. 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

13. Responding to FDA/CFDA Deviations
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 re-occurring

14. Prepare Your Organization for FDA Inspections
4/22/2017
Prepare Your Organization for FDA Inspections
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

15. Examples Response to 483 too late Respond within 15 days
4/22/2017
Examples
Response to 483 too late
483 received on August 26, 2010
We acknowledge your written response, dated September 23, ,, 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
Respond within 15 days
(253)

16. Inadequate Response to 483
4/22/2017
Example
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.
 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..
Time frame
Details how to
(253)

17. Inadequate Response to 483
4/22/2017
Example
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.   .
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.
Extend to all balances

18. Deviation: HPLC for Testing of xx not Qualified
4/22/2017
Deviation: HPLC for Testing of xx not Qualified
Corrective Action
Preventive Actions
Qualify that specific HPLC
Details How to qualify?
Other HPLCs in the lab?
Other
Lab Equip-ment?
Time frame?
Training
Impact on other tested products?
Other labs?
Global
Approach?

19. Responding to 483s/ Warning Letters
Examples
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

20. 4/22/2017
Workshop Overview
Small groups of attendees review most frequently cited FDA Warning letters/483’s related to laboratory controls
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
Groups present the outcome to the entire audience (In english or Japanese)

21. Free Resources PPT Presentations 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
(available until September 30, 2014
PPT Presentations

22. Thank You I would like to thank All attendees for your attention
Agilent Technologies China for invitation and organization
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