How to Avoid FDA Inspection Observations or “483s”

1. How to Avoid FDA Inspection Observations or “483s” Robin M. Fatzinger, RAC Regulatory Affairs Specialist Hogan & Hartson LLP

2. Outline • Background on Inspections • FDA Expectations and Inspections • Preparing for an Inspection • What to do if you are issued a 483

3. Background on Inspections • FDA is a law enforcement agency, whose mission is to protect the public health. • The FDA has broad authority under the Food, Drug, and Cosmetic Act (“FDC Act”) over Biologics, Medical Device, and Pharmaceutical manufacturers. This authority can extend to component suppliers and subcontractors. • An FDA inspection is very different from an audit by a Notified Body, customer or a consultant. • Companies need to be mindful of the FDA’s enforcement authority.

4. Background on Inspections Factors that may increase the likelihood/frequency of Inspections • Recidivism (repeat violations) • Level of risk of products involved • High number or spike in MDRs • Recall • Pending product approval (e.g., PMA) • Long period of time since last inspection • Whistleblower complaint • Trade complaint

5. Background on Inspections Types of Inspections – • QSR • cGMP • Pre-approval • Bioresearch Monitoring • For-cause • Following a recall • Following adverse events • Following whistleblower allegations or trade complaints

6. Background on Inspections – Medical Devices & QSR What is the QSR? • 21 CFR 820 - Codification of Current Good Manufacturing Practices for Medical Devices • Governs: • the methods used in and • the facilities and controls used for • the design, manufacture, packaging, labeling, storage, installation, and servicing of finished devices intended for human use • A standard that is essentially harmonized with international quality standards such as ISO 13485 • Emphasizes quality system, not just a quality department • The principles of the QSR could be applied to ANY business that supplies a product or service to a customer

7. Background on Inspections – Medical Devices & QSR Elements of the QSR • Quality Policy • Management Representative • Management Review • Quality System Procedures • Quality Audits • Personnel Training • Design Controls • Document Controls • Purchasing Controls • Production & Process Controls • Acceptance Activities • Nonconforming Product • Corrective & Preventive Action • Etc…

8. Background on Inspections – Medical Devices & QSR Why is it Important to Comply with the QSR and other Quality and Manufacturing Regulations? • Regulatory Reasons • FDA has a wide range of enforcement actions that it can take against you and your company. • These actions can disrupt your business, create negative publicity and cause customer relations problems.

9. Background on Inspections – Medical Devices & QSR Types of Actions that FDA Can Take: • Issue 483 • Issue Warning Letter • Request or Require Company to Recall Products • Withdraw PMA Approval • Seize Product • Withdraw License • Enjoin Your Company • Impose Civil Penalties • Criminally Prosecute Individuals

10. Background on Inspections – Medical Devices & QSR • Business Reasons • Recalls are expensive • Repairs/refunds are expensive • Poor yields, inefficient processes, are expensive • Enforcement actions can have a negative impact on your company in the marketplace and on Wall Street

11. Background on Inspections – Medical Devices & QSR • Other Good Reasons • Compliance Promotes Good Relationship with FDA, and vice-versa • Failure to comply could result in harm to patients (The patient could be you or someone you know!)

12. FDA Expectations & Inspections Quality System Inspection Technique (QSIT) Inspection Strategy • Focuses on the following subsystems: • Management Controls • Design Controls • Corrective & Preventive Action Systems (CAPA) • Production & Process Controls

13. FDA Expectations & Inspections Quality System Inspection Technique (QSIT) Corrective & Preventive Actions Design Controls Production & Process Controls Management Controls Equipment & Facility Controls MaterialControls Records, Documents, & Change Controls

14. FDA Expectations & Inspections Themes of QSIT Approach • Top-down approach rather than bottom-up approach • If one subsystem is not in compliance, the entire system is deemed noncompliant • Less emphasis on specific discreet violations and more emphasis on systemic problems • CAPA subsystem considered most critical • Purchasing controls, particularly outsourced processes, has become a focus for FDA recently

15. FDA Expectations & Inspections What FDA may look at before starting inspections • Prior Establishment Inspection Reports (“EIRs”) • Prior FDA-483s • Prior Warning Letters • MDR database • Prior Recalls • 510(k)s or PMAs • SOPs provided by company

16. FDA Expectations & Inspections What Does FDA Expect? • Commitment to quality that starts with management and permeates throughout your company (“company culture” that is quality-minded) • Written procedures and work instructions that • Cover every QSR provision applicable to your company • Reflect your company’s practices • Records (objective evidence) showing that you follow your procedures. Document what you do; do what you document

17. FDA Expectations & Inspections Common Pitfalls • Production and Process Changes • “Small” changes introduced by “helpful” employees • Process grouped together without assessing impact • Sequence and timing changes • Undocumented deviations • Environmental Control • Temperature requirements not met • Cleanliness not maintained • Common practices, rather than documented processes • Gowning requirements • Protect the product and/or protect the employee • Inconsistent application

18. FDA Expectations & Inspections What Does FDA Expect? • Quality subsystems that are linked (connect the dots!) • Analysis of and timely reaction to all sources of quality data • Responsiveness to problems; closure of open items (close the loops!) • Consistent (daily) compliance

19. FDA Expectations & Inspection Common Pitfalls cont. • Equipment • Calibration and user standardization not conducted • Set-up not verified or documented • Incomplete change-over from previous production activity • Manufacturing Material • New material – “Everyone knows that olive oil works better than machine oil.” • New supplier - “It’s the same thing, just from a different source.” • Inspection, Measuring and Test Equipment • Use of the wrong tool for the right job • Calibration or standardization not verified

20. FDA Expectations & Inspection Common Pitfalls cont. • Process Validation • Lack of meaningful limits • Specifications not based on critical parameters • Performance not assessed at both extremes • Failure to calibrate equipment/instruments uses in validation testing • Failure to follow current SOPs • Failure to establish protocols that meet FDA’s expectations (batch sizes, no. of runs, etc.) • Failure to explain deviations • Failure to investigate nonconformities • Failure to approve protocol in advance of conducting validation study

21. FDA Expectations & Inspection Common Pitfalls cont. • Records/Documentation • Failure to document critical information • Use of  mark instead of recording required raw data

22. Preparing for an Inspection BE PREPARED!

23. Preparing for an Inspection Quality Culture • No need to create separate ISO and QSR systems but be sure that your system is fully compliant with the QSR. ISO certification  successful FDA inspection. • Company culture should embody QSR and encourage daily compliance. • Get management’s commitment to dedicate necessary resources and personnel to ensure the “quality” of the quality system. • Get executive management to establish and review quality objectives.

24. Preparing for an Inspection • Understand FDA’s motivations. What is the purpose of the inspection? • Conduct frequent internal audits and mock inspections as if you were an FDA investigator. • How would FDA likely react to certain issues / documents? • Does the company’s documentation tell a story that is clear and convincing? • Does documentation “stand on its own”? • Does the information in the file support the company’s decisions? • Consider third party audits to obtain more objective viewpoint.

25. Preparing for an Inspection Training • Ensure that personnel are trained on FDA’s requirements and expectations and how to handle inspections. • Ensure that personnel are familiar with FDA’s QSR regulation, QSIT manual and other relevant guidances. • For example, appropriate personnel should review the QSIT Manual and be prepared to answer each question addressed. • Use terminology familiar to FDA (e.g., use design control terminology as opposed to the company’s own language for design control concepts). • Refer to guidance documents to understand what FDA is looking for in the company’s procedures. • Firm should have a written inspection procedure and train personnel to follow it.

26. Preparing for an Inspection Training cont. • Instruct all employees who have a quality /manufacturing function to: • Clean-up their work place and their work environment (no post-it's, obsolete documents, food, music, ... ). • Be ready to explain in their own words the quality policy and what this means to them. • Be prepared to explain how they were trained to do their job. • Use their approved procedures to explain what they do. • Make the investigator follow any procedures that the employee is expected to follow (e.g., wearing goggles, proper gowning procedures, etc.). • Be truthful and accurate. • Base answers on facts.

27. Preparing for an Inspection Training cont. • Instruct all employees who have a quality / manufacturing function NOT to: • Lie to an FDA Investigator. • Argue or get up tight with the investigator. • Answer questions that the employee does not understand. • Guess or speculate. • Offer additional information.

28. Preparing for an Inspection Review Prior Commitments • Review prior 483s and Warning Letters and be prepared to explain how the company corrected each deficiency. • Did you meet all of the commitments that you made to FDA in prior 483 and Warning Letter responses? If not, you may lose credibility with the agency. • Organize responsive documents in an orderly fashion such as a 3-ring binder.

29. During the Inspection • During the opening meeting, review with the investigator relevant company policies and programs. • Executive management should attend the opening meeting and provide opening comments, if at all possible. • If the investigator is not familiar with the company and its products, provide a brief presentation of the company’s product lines, organizational structure and the manufacturing and quality operations that are performed at the subject facility. • Understand the investigator’s question before providing an answer. If necessary, ask for an explanation. Refer questions to the most appropriate employee. • Deviations noted by the investigator should be corrected as soon as possible. • Be careful not to over-commit to taking corrective actions before considering their impact and necessity.

30. During the Inspection • Keep duplicate copies or samples of materials given to (or photographs taken by) the investigator. • Take copious notes of questions asked, responses given and issues raised. • Ask for daily wrap up sessions; ask what observations have been identified and what areas the investigator expects to cover the next day. • Close loops before the end of inspection (e.g., follow-up on open issues, provide documentation requested).

31. During the Inspection • During the exit interview, make sure that all deviations are adequately discussed. If there is disagreement, present all of the supporting information including cited regulations and official interpretations that support the company’s viewpoint. • Make sure that you understand the investigator’s viewpoint before he/she leaves. • Request that the investigator annotate the 483 appropriately. • Do not sign affidavits if requested.

32. What If You DO Get a 483? • FDA Form 483 is a list of observations that the inspector found to be objectionable. May be nonconformances with the FDA regulations. But the company may be able to convince FDA that the observation is not a nonconformance. • Common observations on Form 483 include: • Failure to follow SOPs • Inadequate complaint files/failure investigations • Failure to file Medical Device Reports (MDRs) for adverse events • Failure to report field actions under 21 CFR Part 806 • Failure to follow design controls for product modifications • Failure to conduct internal audits • Failure to take timely and adequate corrective actions • Inadequate training • Process validation issues • Failure to implement adequate CAPA system

33. What If You DO Get a 483? • Immediately submit to FDA a written reply to the FDA Form 483 that addresses all of the observations. • State how and when you expect to make corrections. • If you disagree with an observation, give reasons and references to regulations, guidances, or other FDA documents, to support the company’s position. • Include supporting documentation with response (revised SOPs, training records, etc.). • Keep in mind that the person reviewing the response may not be the person who visited your facility. Provide the proper context of the inspectional observations and the company’s responses. Do not assume that the reviewer understands the context in which the observations were made. • Be reasonable in setting schedules for corrective actions. Do not over commit or unnecessarily prolong completion schedules. • Tone is important.

34. What If You DO Get a 483? • General Advice • Effective introduction – state that the company takes the issues seriously • Restate FDA’s inspectional observation and provide response immediately following. • Address systemic actions being taken to address the quality system observations (e.g., third party audits, staffing changes, company-wide training, etc.). • Be sure that the response not only addresses what is being done, but HOW the company’s actions address (or will address) FDA’s observation.

35. What If You DO Get a 483? • General Advice cont. • When practical, copy and paste any revisions to an SOP into the response. • If an SOP has been revised, attach it to the response. • If training has been conducted as part of the corrective action, attach a copy of the training records. • If an action will be completed in the future, provide the date by which it will be completed and commit to provide evidence of implementation (e.g., SOP, training records, etc.). • Address only the observations cited by FDA. Do not expose other potential vulnerabilities in your quality system. • Keep FDA apprised of progress in meeting deadlines.

36. Resources • FDA Website – Device Advice http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ComplianceActivities/default.htm • Preamble to Quality System Final Rule • FDA's QSR Manual • The FDA and Worldwide Quality System Requirements Guidebook for Medical Devices, Kimberly Trautman (1997) • Global Harmonization Task Force (GHTF) Guidance Documents • Trade Press/Conferences • Warning Letters Issued to Competitors • Industry Standards • Common Sense

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