November 2003 Slide 1 PHARMACEUTICAL REGULATORY AND COMPLIANCE CONGRESS AND BEST PRACTICES FORUM MANUFACTURING AND GMP ISSUES: PREPARING FOR AN FDA INSPECTION ARTHUR N. LEVINE ARNOLD & PORTER November 2003

Slide 2 CONSEQUENCES OF POOR GMP INSPECTIONS n Voluntary product recalls, alerts, temporary cessation of manufacture or distribution n Increased FDA oversight n re-inspection n inspection of other sites n heightened attention to ADEs and other reports n FDA regulatory action n Significant inspectional observations n Warning letter n “Compliance hold” on pending NDAs and supplements, and exports n Disruption of clinical research n Withdrawal of NDA n Seizure, injunction, criminal prosecution

November 2003 Slide 3 ADDITIONAL IMPACTS n Revised processes and procedures n Adverse government contract decisions n Disruption of contractual obligations n Reassessment by the business/investment community n Strains on employee morale n Adverse publicity n Increased product liability exposure n Shareholder suits n False Claims Act suits (implied certification)

November 2003 Slide 4 THE REASONS FOR POOR GMP INSPECTIONS n Inadequate QA n QA authority and resources n Training n Supervision n SOPs and document control n Shared understanding of quality objectives n Performance n Financial support n Inadequate management controls over operations and quality n Establishing the corporate compliance culture n Communicating the corporate compliance culture n Enforcing accountability n Clearly identified responsibility

November 2003 Slide 5 n Ineffective auditing and monitoring n Unclear or inadequate documentation/inadequate change control n Poor validation n Failure to recognize indicators of manufacturing or quality system problems n Weak mechanisms of preventive and corrective action n Unresolved cGMP deficiencies (“repeat violations”) n Inadequate preparation for FDA inspection

November 2003 Slide 6 FDA GMP Inspections n Bottom-up inspections n recalls/alerts n OOS findings n OOS/manufacturing error investigations and reports n QA release decisions n QA/manufacturing changes n environmental excursions n CAPA n Top-Down Inspections n management controls n quality reports and reviews n quality unit authority/quality system infrastructure n quality manual/documentation n training processes n validation/process control system

November 2003 Slide 7 FDA GMP INSPECTION REALITIES n Demonstrating a “state of control” n Your GMP compliance is what it is n Performance often lags behind system controls n Documents speak for themselves n Exercising good communication n Being responsive to investigator requests n Daily meetings/daily reports n Avoiding 483 surprises

November 2003 Slide 8 FDA GMP INSPECTION ISSUES n Perceived failure to fully correct previous observations or fully meet prior commitments n Perceived lack of candor n Perceived lack of compliance with SOPs n Perceived superficial or inadequate quality operations (e.g., failure to identify and resolve root causes) n Perceived lack of alignment between manufacturing/shipment decisions and quality data n Perceived lack of understanding of quality processes n Investigator expectations exceeding cGMP

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