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

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

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

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) www.fdawarningletter.com

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) www.fdawarningletter.com

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)

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)

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) www.fdawarningletter.com

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 § 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)

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)

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

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

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

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

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, 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 Respond within 15 days www.fdawarningletter.com (253)

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 www.fdawarningletter.com (253)

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

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?

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

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)

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 www.labcompliance.com/agilent (available until September 30, 2014 PPT Presentations

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 Audio: www.labcompliance.com/seminars/audio Video: www.labcompliance.com/seminars/video