PET Drug Inspections and Compliance Update

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Morgan Robbins
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1 PET Drug Inspections and Compliance Update Society of Nuclear Medicine and Molecular Imaging Annual Meeting San Diego, CA June 14, 2016 Krishna Ghosh, MS, Ph.D. Senior Policy Advisor Center for Drug Evaluation and Research Food and Drug Administration

2 Agenda PET drug inspection updates Inspection classifications and trends Deviations/non conformances and OOS investigations PET drug component manufacturing and regulatory expectations 21 CFR Part 212 and data integrity Q & A 2

3 PET Drug Inspections Inspections May 2016 PAI / NDA PAI / ANDA Surveillance Totals

4 PET Drug Inspections Calendar year May2016 6% of PET Sites from 2013/2014 inspections had major compliance issues FDA worked very closely with the manufacturers to get them into compliance Re-inspections were performed to assess the adequacy of the corrective actions All PET re-inspections were completed by Oct 2015, prior to the deadline of Dec 12, 2015 Regular surveillance inspections started from October 1,

5 Inspection Trends 5

6 Outcomes by Inspection Type

7 Inspection Outcomes By Firm Types 7

8 Top Four 483 Observations Jan May

9 Case study Deviations, Non-conformances and OOS Investigations Repeat observations of deviations/non conformance and Out Of Specification(18 events) during last inspection Inconsistency or failure to investigate, unexplained discrepancies and several batch failures Major issues with Cyclotron malfunctions, low yields and synthesis issues with no corrective actions Minimum/ missing written records of deviations/non conformance and Out Of Specification events Some batches released and distributed without any investigations 9

10 Investigations and Corrective Actions 21 CFR Part (b) and (c) Deviation / Non-conformance/ OOS events Recording planned /unplanned deviations Investigating and documenting the event Root cause Identification Corrective action implementation/closure Release of Final Batch Review of deviations/non-conformance Risk assessment /impact to final product Final release of batch 10

11 Investigation of Out Of Specification Results Conduct an initial investigation QC analyst have been investigated laboratory errors have been investigated. If a genuine laboratory error is identified then the OOS result can be invalidated after appropriately documenting the investigation and the root cause. If the initial investigation confirms an OOS was not due to laboratory error, further investigation should be initiated to identify the root cause. Product and materials which are failing to meet specifications should be rejected. An impact analysis must be performed for the earlier batches to assure patient safety. 11

12 Scope of CGMP Inspections for PET Drugs Nonradioactive reagents Reagent kit Ingredient Nuclide generators Synthesis modules 12

13 PET Drug Generator Applications Component and Vendor Controls 21 CFR Part 212 applies to all manufacturers/vendors PAI inspections may be conducted at all manufacturing sites Generator Manufacturers Reagent Kits Radioactive/non radioactive pre-cursors Non radioactive pre-cursors inspected under FDA Compliance manual and API standards Non radioactive reagents/ingredients Automated Elution/software system 13

14 PAI Objectives Objective 3: Data Integrity Batch Failures/Investigations/Trends Objective 1: Readiness for Commercial Manufacturing Process controls Aseptic Process and Media Fills Analytical Tests And Laboratory Controls Objective 2: Conformance to Application New Technology & Process Feasibility 14

15 Data Integrity and Compliance 21 CFR Part 212 CGMP FDA Draft Q and A guidance document April 2016 Access controls for computer Systems List of employees with defined access Controls on programs and methods Shared login unacceptable - ( (c) 10) Electronic Batch Records Actions can not be attributable to individuals Document Control system ( & ) Control of blank forms 15

16 Compliance to 21 CFR Part 212 Audit trails and review (212.20) Activation of all audit trails Frequency based review on risk Acceptance of Electronic copies ( ) Securing metadata Dynamic and static nature of records Paper record retention (212.60) Static and dynamic records 16

17 For More CGMP Information General inquiries Data integrity guidance document 2016 (Draft) atoryinformation/guidances/ucm pdf PET drug web page acturing/ucm htm CDER PET DRUG cgmp Subject Matter Expert : Krishna Ghosh, Ph.D. Krishnakali.ghosh@fda.hhs.gov 17

PAI Inspections, Observations and Data Integrity

PAI Inspections, Observations and Data Integrity Krishna Ghosh, Ph.D. Office of Pharmaceutical Quality Office of Process and Facilities Center for Drug Evaluation and Research November, 2017 20 November