1. Warning Letters – The Forgotten Five
Dan O’Leary CBA, CQA, CQE, CRE, SSBB, CIRM
President
Ombu Enterprises, LLC
OMBU
ENTERPRISES, LLC
©2019, Ombu Enterprises, LLC
The Risk Management File 1
Part G - Statistically Significant Increase

2. Topics Warning Letters Data Analysis Process Validation P&PC
Nonconforming Product
Quality Audit
DHR
Questions
Part G - Statistically Significant Increase

3. Warning Letters

4. Warning Letter Role
When FDA finds that a manufacturer has significantly violated FDA regulations, FDA notifies the manufacturer, usually in the form of a Warning Letter
The Warning Letter identifies the violation, such as poor manufacturing practices, problems with claims for what a product can do, or incorrect directions for use.
The letter also makes clear that the company must correct the problem and provides directions and a timeframe for the company to inform FDA of its plans for correction.
FDA then checks to ensure that the company’s corrections are adequate.
Source: UCM278624

5. Directions and Time Frame
Please notify this office in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to correct the noted violations, as well as an explanation of how your firm plans to prevent these violations, or similar violations, from occurring again.
Include documentation of the corrections and/or corrective actions (which must address systemic problems) that your firm has taken. If your firm’s planned corrections and/or corrective actions will occur over time, please include a timetable for implementation of those activities. If corrections and/or corrective actions cannot be completed within fifteen business days, state the reason for the delay and the time within which these activities will be completed. Your firm’s response should be comprehensive and address all violations included in this Warning Letter.
Source: TEI Biosciences, Inc. 3/6/19

6. Consequences
Failure to promptly correct these violations may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizure, injunction, and civil money penalties.
Also, federal agencies may be advised of the issuance of Warning Letters about devices so that they may take this information into account when considering the award of contracts.
Additionally, premarket approval applications for Class III devices to which the Quality System regulation violations are reasonably related will not be approved until the violations have been corrected.
Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected.
Source: TEI Biosciences, Inc. 3/6/19

7. Warning Letter Close-Out
FDA may issue a Warning Letter close-out letter ("close-out letter") once the Agency has completed an evaluation of corrective actions undertaken by a firm in response to a Warning Letter. A close-out letter may issue when, based on FDA’s evaluation, the firm has taken corrective action to address the violations contained in the Warning Letter. This procedure applies to Warning Letters issued on or after September 1, 2009.
A close-out letter will not be issued based on representations that some action will or has been taken. The corrective actions must actually have been made and verified by FDA. Usually, the standard for verifying that corrections have been implemented will be a follow-up inspection.
Source: UCM278624

8. Data Analysis

9. Scope
The data analysis uses a database of Warning Letters that Ombu Enterprises, LLC maintains
It includes all device Warning Letters from 2008
This is a total of 1,314 Warning Letters
Ombu classifies each Warning Letter using a variety of attributes as shown on the next slide
While Part 820, the Quality System Regulation is the primary source of Warning Letters, other parts are important to a device manufacturer’s QMS.

10. Source The top two sources of Warning Letters are: Inspection 87.7%
Website 9.2%
The remaining sources have very small counts
Billboard appears one time

11. Countries
The top ten countries (there is a tie for tenth place) (I count Puerto Rico separately because it is not a US state) are:
USA 69.86%
China 5.40%
Germany 3.96%
Canada 3.04%
UK 2.13%
Italy 1.52%
Taiwan 1.37%
Japan 1.22%
Puerto Rico 0.84%
France 0.76%
South Korea 0.76%

12. Outside Expert Consultant
31 Warning Letters include an outside expert
We are requesting that you submit to this office on the schedule below, certification by an outside expert consultant that he/she has conducted an audit of your establishment's manufacturing and quality assurance systems relative to the requirements of the device QS regulation (21 CFR Part 820).
You should also submit a copy of the consultant's report, and certification by your establishment's Chief Executive Officer (if other than yourself) that he or she has reviewed the consultant's report and that your establishment has initiated or completed all corrections called for in the report.
The initial certifications of audit and corrections and subsequent certifications of updated audits and corrections (if required) should be submitted to this office by the following dates: [redacted]

13. Detention 98 Warning Letters include detention
Given the serious nature of the violations of the Act, devices manufactured by your firm are subject to refusal of admission under section 801(a) of the Act, 21 U.S.C. §381(a), in that they appear to be adulterated. As a result, FDA is taking steps to refuse entry of these devices into the United States, known as “detention without physical examination”, until these violations are corrected. In order to remove the devices from detention, your firm should provide a written response to this Warning Letter as described below and correct the violations described in this letter. We will notify you regarding the adequacy of your firm’s responses and the need to re-inspect your firm’s facility to verify that the appropriate corrections and/or corrective actions have been made.

14. Parts Warning Letters often cite multiple parts of the regulations.
The percentages below are for Warning Letters that cite any section of the part.
For example, a Warning Letter that cites five sections of Part 820 would be counted one time in this list.
801 Labeling 0.93%
803 MDRs 29.67%
806 Corrections & Removals 5.92%
809 IVD 0.12%
812 IDE 2.65%
820 QSR 60.27%
821 Tracking 0.12%
822 Postmarket Surveillance 0.31%

15. QSR Sections The top ten cited QSR sections are: 820.100 CA & PA 13.3%
Complaints 11.5%
Design Control 10.5%
Acceptance Activities 7.0%
Purchasing Controls 6.8%
Process Validation 6.5%
P & PC 6.2%
Nonconforming Product 5.4%
Quality Audit 5.4%
DHR 5.2%
If the analysis included other parts and sections, the MDR Procedures would fit between Design Control and Acceptance Activities
It represents 87.3% of all Part 803 citations

16. § Process Validation

17. Historical View

18. Process Validation Validate Perform Revalidate Qualified Operator IQ
Review
Control Methods OQ
Evaluate
Data Collection PQ
Revalidate
Major Equipment

19. Requirements §820.75 has three subsections
§820.75(a) states when a process requires validation, the expected results, and the documentation
§820.75(b) provides the requirements to operate the process after validation
§820.75(c) explains the conditions for revalidation

20. Expectations Validate a process when the output is not fully verified
Processes where the verification test is destructive
Processes where the verification test employs a sampling plan
Process validation provides a high degree of assurance that the process output, the product, is conforming
The process capability index, Cpk ≥ 1.33
Process validation determines the process input parameters that ensure only conforming output
A qualified operator monitors, adjusts, when necessary, and records the process inputs

21. Common Problems Problem: Failure to validate a process Countermeasure
Draw a process map of the production process
Include each verification step (see §820.80(c) In-process acceptance activities)
For each verification, document the quantity verified such as: 100%, c=0 sampling plan with 1.0 index value, 0.0%
If the verification step is not 100%, then validate the process

22. Common Problems
Problem: Failure to define the validation sample size to use the defined sample size
Countermeasure
Following § (a) identify the statistical techniques for verifying the acceptability of process capability and product characteristics
Document the specific application of the statistical technique in the process validation protocol
Implement the approved protocol and create the associated quality records

23. Common Problems
Problem: Failure to create procedures for monitoring and control of input process parameters
Rationale: Because the process output isn’t verified, the controls must apply to the input parameters, so the operator must monitor and control them
Countermeasure
As part of the procedure for operating the validated process, define the input parameter limits
Ensure the procedure includes the measurement method, the measurement frequency, and when to adjust the parameter (action limits)
Create a data sheet to record the input parameters and whether they were adjusted
Ensure the DHR check includes a check that the data sheet is complete and correct

24. Common Problems
Problem: Failure to re-validate after a specification or standard change
Countermeasure
Establish a procedure for revalidation
Process validation doesn’t expire, it is not calibration
If the process implements a standard, such as an ISO standard, then a new or revised standard could affect the current validation
If there is a design change to a specification, it could affect the process validation
Evaluate each change for its affect on the process
If warranted by the evaluation results, revalidate the process
The revalidation my be partial. For example, a specification change may not require another Installation Qualification
Document the evaluation criteria and the decision

25. § P & PC

26. Historical View

27. Pareto Chart

28. Requirements
P&PC is a collection of diverse topics that may have been sections on their own.
General – Requires processes to ensure that a device conforms to its specifications. This may include process controls such as documented instructions
Production and process changes – Requires that changes use the document control system
Environmental control – Determine environmental conditions that could affect the product and control them
Personnel – Determine personnel contact that could affect the product and control them

29. Requirements
P&PC is a collection of diverse topics that may have been sections on their own.
Contamination control – Determine contaminates that could affect the product and control them
Buildings – Ensure buildings are adequate and have enough space
Equipment – Maintain equipment and document independent maintenance checks
Manufacturing material – Determine any manufacturing material that could affect the product and control it
Automated processes – Validate software used in production and the QMS

30. Common Problems
Problem: Failure to define production controls using documented instructions or procedures.
Note: This is not a requirement, but is commonly cited in Warning Letters
Countermeasure
Identify production processes where deviations from device specifications could occur as a result of the manufacturing process
For each production process determine the methods, techniques, and steps the operator needs to prevent the deviation
Create written instructions and procedures
Control them through document control §820.40
Train the operators on the procedures and create training records

31. Common Problems
Problem: Failure to identify environmental conditions, develop procedures, and create records
Note: Environmental conditions cited in Warning Letters include airborne contamination, humidity, temperature, lighting, static electricity, and pest control
Countermeasure
Do a process audit of each production process looking for environmental conditions that could affect the product
For each identified environmental condition, determine the problem that could occur and the necessary measures to control the environment
Create procedures and work instructions to implement the control measures
Create procedures and work instructions to inspect, adjust, and maintain the environmental control equipment

32. Common Problems
Problem: Failure to validate software used in production processes or the QMS
Countermeasure
Do a process audit of each production process looking for the use of software. Be sure to include software in IM&TE and QC checks. Include procedures and work instructions for the use of software.
Be especially mindful of Excel workbooks
For each software item, identify its control number and revision
For each software item, verify that there is a software validation protocol and report associated with the control number and revision
If not perform software validation

33. Common Problems
Problem: Failure to perform and document equipment maintenance
Countermeasure
Do a process audit of each production process looking for any production equipment. Be sure to include equipment used for in IM&TE and QC checks. Include procedures and work instructions for the use of specific pieces of equipment
For each piece of equipment, identify its make, model, serial number, and control number
For each piece of equipment, ensure the maintenance manual is available
For each piece of equipment, verify that each maintenance activity in the maintenance manual is scheduled in the maintenance program
Verify that each scheduled maintenance activity has been properly performed on time

34. §820.90 Nonconforming Product

35. Historical View

36. Requirements
Establish procedures to control nonconforming product. The procedures include identification, documentation, evaluation, segregation, and disposition
Determine the need for investigation
Notify responsible people about the nonconformance
Document the review and disposition process including responsibilities and authority
For use-as-is, document the justification and the name of the person making the disposition
For rework document in the DHR, the rework, reevaluation, and determination of any adverse effects in the DHR

37. Common Problems
Problem: Failure to establish procedures for control of nonconforming product
Countermeasure
Document a procedure for control and disposition of non-conforming product
Ensure the procedures describes each of the required elements:
Identification
Documentation
Evaluation
Segregation
Disposition
Need for an investigation
Notification of the person responsible (process owner)

38. Common Problems
Problem: Failure to adequately document the use-as-is disposition
Countermeasure
Designate a person to make the UAI disposition
Train the person (and document the training) to evaluate the effect of nonconforming product on the device.
If the disposition is UAI, then the device will be safe, effective, and meet all of its performance specifications
The person making the disposition documents why the disposition does not affect the safety, efficacy, or performance specifications of the device
Document the disposition including the name, signature, and date
Include the documentation in the DHR

39. Common Problems
Problem: Failure to adequately document the rework disposition
Note: Rework ensures the nonconforming product meets the DMR requirements
Countermeasure
For a rework disposition ensure the documentation includes:
A statement of the nonconformity
Identification of the procedure to conduct the rework
The revaluation of the device after rework to demonstrate it meets the DMR requirements
An evaluation of any adverse effects of the rework
Include safety, efficacy, and performance specification
Include the documentation in the DHR

40. § Quality Audit

41. Historical View

42. Requirements
Conduct internal quality audits to assure compliance with QMS requirements and to determine QMS effectiveness
Auditors cannot have direct responsibility for the area audited
Take corrective action, including reaudit, as necessary

43. Common Problems
Problem: Failure to conduct internal quality audits at the frequency in the procedure
Countermeasure
Appoint an Audit Manager, it can be a collateral duty
Identify and train auditors to ensure there is sufficient capacity to conduct the audits
The Audit Manager establishes a schedule of audits distributed over time (typically four calendar quarters)
Assign auditors, conduct the audits, and document the results
Track conformance to the schedule and reschedule missed audits
Report schedule nonconformances at Management Review

44. Common Problems
Problem: Auditors are not independent of the area audited
Countermeasure
Identify and train auditors to ensure there is sufficient diversity to cover the audit areas
For each auditor, identify the location on the organization chart
For each audit area, identify the location on the organization chart
Assign auditors from outside the “vertical” of the area scheduled for audit
For additional independence trade audits with another local company
For additional independence consider an outside consultant
Note: Outside people are subject to purchasing controls

45. § DHR

46. Historical View

47. Requirement
Maintain a DHR for each batch, lot, or unit to demonstrate that the device conforms to the DMR and Part 820.
The minimum content of the DMR is:
The dates of manufacture
The quantity manufactured
The quantity released for distribution
Acceptance records showing compliance with the DMR
The primary identification label and labeling
The UDI or UPC, any device identifiers, and any control numbers

48. Common Problems Problem: Failure to maintain complete DHRs
Countermeasure
Review the DMR to determine the requirements for manufacturing and the expected records
Identify other requirements in QSR such as rework or label verification
Use the review results to create a checklist for the DMR
Train the designated individual in (e) who releases the device for distribution on the checklist
For each lot or batch, review the checklist items for completeness and correctness

49. Questions