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Recent FDA Inspection

Findings and Trends

Jennifer DeMatteo, MCM, CIC

EBAA Director of Regulations and Standards

EBAA Medical Standards

B1.200 Inspections by Official Agencies

Any written documentation of observations, findings, or results (including but not limited to Food and Drug Administration (FDA) Form 483) received by an eye bank which are related to any inspection by an official agency shall be sent to the EBAA office and the Chair of the Accreditation Board within ten (10) business days of receipt. The EBAA office and the Chair of the Accreditation Board shall be copied on all future related correspondence.

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Regulatory Inspections Reported to the EBAA By Month

Number of inspections without Observations Number of inpections with observations

Regulatory Inspections By Region 2009 – 2012 YTD

Region Total No. of Regulatory Inspections

Percentage

Northeast 18 16.51%

Southeast 29 26.61%

Midwest 33 30.28%

Southwest 12 11.01%

West 14 12.84%

Canada 4 3.67%

TOTAL 110

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Regulatory Inspections By Eye Bank Size

Eye Bank Size 2009 2010 2011 2012 YTD

Small 7 10 8 0

Medium 5 15 16 9

Large 10 17 9 4

Total 22 42 33 13

Regulatory Observations

65% 4%

6%

6%

8%

6%

1% 1%

3%

Number of Regulatory Observations 2010 - 2012 YTD

No 483 Issued

1 observation

2 observations

3 observations

4 observations

5 observations

6 observations

7 observations

8 observations

Top Ten Observations Found During

Eye Bank Inspections 2010-2012 YTD

21 CFR Count Description

1271.180 19 Procedures

1271.160 14 Quality Program

1271.195 9 Environmental Controls & Monitoring

1271.55 8 Donor Eligibility Records

1271.230 8 Process Validation

1271.47 7 Donor Eligibility Procedures

1271.260 7 Storage

1271.265 6 Receipt and Distribution

1271.350 5 Reporting

1271.200 5 Equipment

1271.180(a) Procedures

• Procedures appropriate to meet core CGTP requirements for all steps that you perform in the manufacture of HCT/Ps were not established, maintained, defined, documented, implemented, followed, reviewed, revised.

• Specifically, *

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1271.180(a) Procedures

SOPM lacked procedures for:

• Adverse reaction reporting

• Error and accident reporting (HCT/P deviations)

• Archived specimens

• Procedure for testing both infant donor and mother

• Validation of insulated transport boxes

• Receipt, storage and release of ocular tissue for research & education

• Physical exam of ocular donors

1271.180(a) Procedures Procedures were not followed: • Environmental monitoring to validate processing was done in a way

to prevent contamination.

• Dates of training completion is not recorded on training record per SOP.

• Entries in cleaning log and environmental culture documentation was not corrected per procedure.

• Gloves & gowns not worn when handling tissue per SOP

• Record retention

• Aseptic technique

• Supervisory approval of SOP variance

1271.180 Procedures

SOP Maintenance • SOPs are not kept up to date.

• SOP for lab excision doesn’t reflect current practice – states LFH and excisions are done in a clean room.

1271.180(b) Review and Approval • SOP Manual doesn’t contain documented approval of procedures by the

director. – 2 findings.

1271.160 Establishment & Maintenance of a Quality Program

A quality program which addresses all of the core CGTP requirements, appropriate for the HCT/Ps manufactured and the manufacturing steps performed, has not been established, maintained, defined, documented, implemented, followed, reviewed, revised.

Specifically, ***

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Quality Program Observations 1271.160 (a) General

• Expired SOPs were not removed

1271.160(b)2 – Procedures

• No procedure for the approval of the validation and verification of software.

• No procedure for monitoring distribution

1271.160(b)3 – Corrective Actions

• No CA’s for missing recipient information

• No CA for incomplete autopsy findings

• No CA for incomplete plasma dilution sections

• CA for complaint about melted ice was not implemented.

Quality Program Observations

1271.160(b)6 – HCT/P Deviations

• No investigation when med/soc history SOP was not followed

• Investigation of error in marking pre-transfusion blood samples did not correct written specifications for adequacy of specimens or include test inserts and lab procedures

• Investigation of inadequate sterilization did not include CA’s – review of time/temp before use of equipment and change in SOP

1271.160(c) – Audits

• Periodic quality audits were not performed, specifically audits of establishment performing DRAI. (x2)

• No RCA or follow-up audit performed for issues with storage/monitoring of supplies or tissue found without a donor number.

• Periodic audit by direct observation not performed.

1271.195 - Environmental Controls and Monitoring

1271.195(a) – Environmental Control

• Didn’t provide adequate temperature control. No explanation or CA for out-of-range temperatures.

1271.195(c) – Environmental Monitoring

• No monitoring of environmental conditions for microorganisms before, during, and after processing corneas. (x2)

• No rationale for 25 CFU threshold for settling plates within LFH or used for touch plates.

• Microbial monitoring doesn’t specify which organisms warrant investigation.

1271.195 - Environmental Controls and Monitoring

1271.195(d) – Records

• Documentation of environmental controls/monitoring was not maintained – ATTEST documentation not maintained.

• 14 of 16 biological indicators for adequacy of sterilization of processing equipment were read at less than the hour required.

• SOP on biological contamination control directs sampling take place according to two diagrams, which aren’t included in the procedure.

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1271.55 - Donor Eligibility Records

1271.55(a) Accompanying Records

• No DE or slit lamp evaluation documentation accompanied tissue - EB contracts with another facility for evaluation and release of tissue.

1271.55(b) Summary of Records

• Accession numbers for specimens not kept in a logbook

• Documentation of name/address of communicable disease testing lab not maintained

1271.55 - Donor Eligibility Records

1271.55(d) Record Retention Requirements

• Records were not retained for 10 years (x3) – Third party records used for DE were destroyed 6 months after DE was determined

and quality reviews were complete.

– Records were purged after DE determined and tissues were distributed.

– Deleted email with DE document and failed to retain a paper record in the donor file. Contracted establishment purges all paper, computer, and tape records w/in 30 days.

• No documentation to explain why donor was accepted when there were possible contraindications

• DE records were not accurate, indelible, and legible – Numerous (9 of 25) discrepancies between recording and hard copy questionnaire.

1271.230 Process Validation

Procedures to validate and approve processes that cannot be fully verified by inspection and tests were not established, defined, and documented.”

Specifically ***

1271.230 Process Validation

• EK precuts were not validated to ensure no microbial contamination before, during, and after cutting corneas (x3)

• Tissue transfer from one storage chamber/media vial to another is not validated.

• No SOP exists describing steps for freezing scleral tissue until tissue is thawed and fully processed/preserved.

• Validation of tissue cultures doesn’t assess antibiotics in media to prevent false positive cultures.

• A validated process that was changed was not reviewed, evaluated, and revalidated, Specifically, the electronic system used for labels was not revalidated.

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1271.47 Donor Eligibility Procedures

Procedures for all steps in testing, screening, and DE determination were not established, maintained, defined, documented, implemented, followed, reviewed, revised.

Specifically, ***

• Distribution SOP mentions a form and not the software database currently used.

• DE procedures were not followed (x3) – Tissues from a donor with bacteremia and another with a pig valve were released.

– Didn’t follow Physician Consultation procedure and used consults from a 3rd party MD who was not involved in the donor’s care to support acceptance of the donor.

– Abbreviated med/soc questions

– Corneas recovered despite military travel and sepsis documentation

1271.47 Donor Eligibility Procedures

1271.47(d) Departures from procedures

• No justification recorded for deviating from donor eligibility procedures.

• A determination that a BPD did not increase the risk of disease transmission was not made by a responsible person prior to distribution. Specifically, DRAI indicates that donor received blood products prior to death, but there is no further documentation or medical record review. There was verbal information regarding 1000 ml NS, but no medical records were obtained to verify volume.

1271.260 - Storage

1271.260(b) Temperature

• Temperature verification of insulated eye box not performed.

1271.260(d) Corrective Action

• No report or CA taken when refrigerator temperature were out of range.

• No documentation of CA when corneal shipment was delayed due to winter weather – no assurances that temperature was maintained.

1271.260(e) Acceptable Temperature Limits

• Storage temperature for media refrigerator not recorded for one week.

• Recorded storage temperatures not routinely reviewed to ensure temps are w/in acceptable limits. No documented comparison between digital display, temp chart recorder, and manual thermometer per SOP.

• No scientific documentation for storage at -70°C.

1271.265 Receipt and Distribution 1271.265(a) Receipt - No documentation of eye tissue inspection & condition of

returned tissues for damage or contamination.

1271.265(c) Availability for Distribution

• Tissues sent out for processing before distribution did not have a review of manufacturing and tracking records prior to release.

• Release criteria not verified before tissue made available for distribution. Documentation shows tissue was shipped on March 2 but DE determination was Mar 3 – due to paper and electronic documentation.

1271.265(d) Packaging and Shipping - no validation of insulated transport boxes

1271.265(e) Procedures – Procedure does not specify quantity of ice to place in shipping container

1271.265(f) Return to inventory – Neither the Procedure nor Assessment Form mentions that a media color change may be indicative of bacterial contamination.

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1271.200 - Equipment

1271.200(b) Procedures and schedules

• Dates not recorded on temperature monitoring charts

• Biological indicator results recorded at different time intervals than SOP requires; documentation indicates not read at the correct time, often days later.

• No instructions for calculating acceptable centrifuge calibration ranges

1271.200(e) Records

• SOP states that LFH cleaned once a week and before and after each use but no documentation found for cleaning before processing use on 3 occasions.

• Failure to document reasons and troubleshooting for sterilization cycle failure.

• Failure to document centrifuge calibration.

1271.350 - Reporting

• Adverse reactions SOP did not include notification and reporting

• HCT/P deviations were not reported to the FDA (x2) – Temperature control deviation

– Shipment delay

• Error/accidents not detected prior to tissue release were not reported to the state – Med/soc questions were unanswered.

• Deviations related to distributed HCT/Ps were not investigated after a shipment delay.

Less Frequent 483 Observations 1271.150(c) Manufacturing Agreements

• Contracted donor screening but did not verify that scanned questionnaire matched original form or that the interview matches the audiotape.

1271.170 Personnel

• SOP doesn’t delineate the person responsible for each procedure.

• SOPM doesn’t contain protocol for periodic review by user personnel – no documented review in training file of QA personnel.

• No training documentation on updated P&Ps for out of town technicians.

• Personnel have not been trained as necessary to perform their assigned responsibilities. Multiple instances of failure to log tissue recoveries and no training documentation for the use of this form in training files.

1271.190 Facilities

• Facility did not provide adequate plumbing with hot water.

FDA Form 483 Observations 1271.210 Supplies and Reagents

• Supplies / reagents not stored per manufacturers instructions (x2)

• Supplies / reagents were used before they were verified to meet specifications (x2) – Expired reagent used to clean BSC prior to tissue processing; temperature storage issue.

1271.220 Processing and Process Controls

• Technician contaminated sterile forceps with wet autoclaved turbine box during corneal processing.

1271.250 Labeling Controls

• Discrepancy found between donor ID number and cornea ID number

• Labels on coolers missing a label that they contain human tissue

• Package insert didn’t include all required information

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1271.270 Records

• No agreement with processing eye bank – listing names, addresses, services, and responsibilities of that establishment.

• SOP not followed regarding timeframes of reporting and investigation of NCR, lacked dates and signatures, NCRs without root cause identified or further investigation conducted.

1271.290 Tracking

• Tracking system did not document disposition of each tissue. Tissue discard log didn’t account for 15 discarded corneas; they were instead documented within each donor’s file.

1271.320 Complaint File

• Complaints received were not maintained in a file designated for complaints.

• Complaint file contained insufficient info for review & evaluation – no RCA performed; surgeon was not notified

• Complaints were not reviewed and evaluated to determine if complaint was related to a deviation or AR. No investigation documented for complaint related to an AR, and no Medical Director review/evaluation.

1271.50 Donor Eligibility Determination

• No SOP for DE determination and delegated authority

• Med/soc history forms screen wrong time frame for receipt of human-derived pituitary growth hormone.

• Pediatric donor suitability questions asked of mother but not donor regarding sexual history and incarceration.

1271.60 Quarantine

• Quarantined tissue not labeled as required

• Tissue shipped for processing was not shipped in quarantine.

1271.75 Donor Screening and 1271.80 Donor Testing

• A second DRAI performed but not maintained by firm or contractor.

• Donors with risk factors were not determined to be ineligible; specifically hepatitis history and bovine heart valve.

• RPR testing done on plasma samples stored longer than 48 hrs.

Less Frequent Observations

1271.26 Registration Changes

• Failure to notify State DOH of changes in registration information (address change) within 30 days.

1910.1030 Bloodborne Pathogens

• Failure to label storage area with the universal biohazard sign.