SJN DO CB Field Alert Reports. Edwin Ramos Director of Compliance Food and Drug Administration San Juan District Office

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1 SJN DO CB Field Alert Reports Edwin Ramos Director of Compliance Food and Drug Administration San Juan District Office

2 SJN DO Mission Assuring that safe and effective drugs are available to the public Reduce public health risks associated with the quality, safety, and effectiveness of the nation's marketed drugs High-quality pharmacovigilance and risk minimization practices Utilize strategic problem solving to identify, evaluate, and prioritize risks related to drug quality, safety, effectiveness, and availability

3 SJN DO CB Review the Violations Analyze the Violations Consider Desired Outcome Optimize Compliance Decisions Pursue Compliance Decision with Energy Follow 7 Cardinal Rules

4 Review the Violations SJN DO CB Evidence collected Regulatory significance of each observation DP risk analysis or immediate HH Analyze the Violations Examine evidence Impact to FDP Identification of relevant agency policy Determine adulteration charge provisions of law and regulations Develop a charging scheme

5 SJN DO CB Consider the Desired Outcome Compliance with Pre-approval Regulation Manufacturing Regulation Post-approval Regulation Removal of adulterated, misbranded or unapproved drug products from market or withhold approval Optimize Compliance Decision HH of product on the market, if necessary History of significant, uncorrected violations Significant violations but no immediate HH or violative history

6 SJN DO CB Pursue Decisions with Energy Compliance Actions are taken for violations of law Law is in place to Promote and Protect Public Health Desired outcome is, must be a top priority Follow 7 Cardinal Rules of a Compliace Officer

7 SJN-DO Legal Actions FY 2009 Warning Letters Issued: 11 Food: 6 Medical Gas: 1 Devices: 2 OTC: 1 Blood Bank: 1 Untitled Letters Issued: 2 Food - 2 Regulatory Meetings: 5 Food: 2 OTC: 1 Post-WL Devices: 2 Post-WL

8 WL Close-Out Letter Program WL issued after September 1, 2009 When based on FDA s s evaluation the firm has taken corrective actions Corrective actions must have been implemented by firm and verified by FDA DO will issue the close-out out letter? - WLcloseoutprocess@fda.hhs.gov

9 21 CFR effective 5/23/85 PART APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Sec Other postmarketing reports. (a) Applicability. Each applicant shall make the reports for each of its approved applications and abbreviated applications required under this section and section 505(j) and section 507(g) of the act.

10 The report and its mailing cover should be plainly marked: NDA--Field Alert Report'' (i) Information concerning any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article. (ii) Information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug product, or any failure of one or more distributed batches of the drug product to meet the specifications established for it in the application.

11 (b) Reporting requirements. The applicant shall submit to the FDA at the specified times two copies of the following reports: (1) NDA--Field Alert Report. The applicant shall submit specific information about distributed drug products to the jurisdictional FDA DO that is responsible for the facility involved within 3 working days of receipt by the applicant.

12 21 CFR (1)(i) Required Reporting Any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article Confirmed and unconfirmed products

13 21 CFR (1)(ii) Required Reporting Bacterial contamination Significant chemical, physical or other changes Product deterioration Product out-of of-specification

14 Primary Defects Reported Delivery System 10% Examples Fill problem 4% ADR 18% Contaminated/ sterility 3% Formulation/ substitution 22% Other 9% Packaging 6% Labeling Product defect 14% 14

15 Reporting Requirements Applicant holders are required to submit NDA/ANDA FAR on drug products manufactured or distributed within or outside the U.S. U.S. Office/Agent - responsible for reporting to jurisdictional FDA DO (registered or located) Notify the DO within 33 working days

16 Reporting Requirements Information may be provided by telephone or other rapid communication means, with prompt written follow-up Form FDA 3331 standardized form Internet Availability cder.html

17 Changes to FDA 3331 Line 13- include Root Cause(s) ) of the Problem(s) ) in an effort to obtain more info from the applicant and better assess the problem Compliance Program , Drug Quality Reporting System, NDA FAR is being revised

18 33 Working Days Required to Report Regulatory Clock Begins: Firm becomes aware of a reportable problem Complaint Internal testing Unconfirmed problem Confirmed problem

19 FAR Required Firm Reporting Further investigation required Determine the root cause Corrective action initiated e.g., formulation revision, labeling change Product Recall FAR is not Required Problem is resolved within 3 working days, such as, analytical lab error

20 Investigation Date/OOS #/Brief Subject Heading Author/investigator Product name/affected lot number (s) Clear statement of the reason for investigation Root cause analysis of investigation Evaluation of impact on previous and subsequent lots Personnel interviews Audit of procedures, records, and lab-books books Conclusion - root cause of OOS (if found) Corrective/preventive actions, if needed

21 Investigation For those extending beyond the lab must follow an outline with particular attention to corrective action. The firm should: State the reason for the investigation Provide recap of the process sequences that may have caused the problem Outline CA necessary to save the batch and prevent similar recurrence rence List other batches/products possibly affected, the results of investigation of these batches and products, and any corrective action Specifically: examine other batches of product made by the errant employee or machine examine other products produced by the bad process or operation preserve the comments and signatures of all production and QC personnel who conducted the investigation and approved any reprocessed material after additional testing

22 District Responsibilities Submit a copy of each FAR Initial within 5 working days Follow-up in a timely manner Final Upon receipt and district evaluation

23 District Responsibilities Submit DO action plan Available investigational information Assess significance of FAR Conduct appropriate follow-up Determine compliance with regulation Routine inspections Pre-approval inspections

24 District Responsibilities Receive all FARS Designates a Drug Field Alert Monitor Assess significance of FAR FAR complies with regulation Evaluates firm s s root cause analysis & CAPA Monitors the progress and completion of the firm s s CAPA Forward FARs to CDER/DCRMS within 5 working days after receipt

25 District Responsibilities Request from applicant holder: Laboratory reports Investigational reports Sample collection Other documents with info used to Id or determine root cause of the problem Time lines for initiating and completing investigations, if needed.

26 Division of Compliance Risk Management & Surveillance Program Team Rapidly identify all potential health hazards associated with product use Detect industry problems and trends Unacceptable risks identified Operate a centralized reporting system

27 DCRMS Program Team Liaison between DO and CDER Manages all NDA FARs Coordinates inspectional & regulatory activities Receives all domestic and foreign related FARs and enters into DQRS database for further evaluation

28 DCRMS Program Team Evaluates all FARs,, EIR, & corrective actions Consults with appropriate CDER Review Divisions Provides consults/guidance to DO Monitors progress & completion of related investigations & corrective actions Recommends/approves appropriate regulatory action re: firm s s failure to comply with 21 CFR (b)(i)(ii)

29 DCRMS Workflow Receive Report Code Defect Code Severity Determine further actions Enter Report In Database Send Report to District Company Other Offices Issue Assignment if needed Follow-up

30 DCRMS Program Team Screen all reports Responsibilities Review/Evaluate Potential Health Hazard Prioritize Priority 1 - Imminent or serious health hazard Priority 2 - Potentially significant cgmp problems Priority 3 - Routine follow-up

31 CDER OC HFD-330 Approves regulatory actions re: FAR reporting Warning Letter, if appropriate Significance of violation(s) Previously cited violation(s) Concurrence with HQ

32 WL Citation Example Failure to submit NDA Field Alert Reports (FAR) within 3 working days of becoming aware of information concerning any significant chemical, physical, or other change or deterioration in the distributed drug product as required under 21 CFR For example, regarding the unknown peaks that were detected for Product A and Product B, your findings from the inspection show that the unknown peak was initially identified in June 2008 and your investigation of this peak was approved and closed by your firm in August However, the FAR was issued on November, 2008, during the FDA's inspection of your facility. Neither the records reviewed by the investigators, nor the information submitted with your response to the FDA-483 includes a justification or rationale for your decision to not submit a FAR to the FDA's SJD DO in a timely manner

33 WL Citation Example 1. For example, the agency was not notified, in accordance with NDA Field Alert reporting requirements, when it was determined that lot 1234, ERR Tablets USP 0.10 mg, failed impurity and dissolution testing at the 9 month of prescribed stability testing interval as reported for your on-going LT room temperature stability study.

34 CDER Review Divisions Responsibilities Review FAR Determine completeness for review Assure any corrective action(s) ) is not in conflict with NDA/ANDA requirements Assures that a supplement has been submitted and approved for the NDA/ANDA FAR becomes part of the approved NDA/ANDA 34

35 Promoting and Protecting Public Health The intent of the 21 CFR regulation is to establish an early warning system so that significant problems are brought to the Agency's attention by applicant holders in order to prevent potential safety hazards from drug products already in distribution.

36 Impact on Public Health Protection Recalls (types see 21 CFR Section 7.3) Corrective Actions Discontinuation of products