Ask the Quality Regulatory Experts

Dennis A. Gastineau

Mayo Clinic

24 May 2010

Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

Incorporation

• Non-profit corporation co-founded in 1995 by the International Society for Cellular Therapy and the American Society for Blood and Marrow Transplantation

• Establishes standards for high quality medical and laboratory practice in cellular therapies

• Conducts voluntary inspection and accreditation in the field of cellular therapy

International Expansion

• Collaboration with EBMT and ISCT-Europe to establish JACIE

• Goal of JACIE is to improve quality of HPC transplantation in Europe through its accreditation and education programs, and to work toward international harmonization of standards and regulations

• Collaboration with NetCord to draft comprehensive international standards for cord blood and a parallel accreditation program

• NetCord is an international network of independent cord blood banks

Timeline

• 1995: Initially founded as the Foundation for the Accreditation of Hematopoietic Cell Therapy (FAHCT)

• 1996: First edition of FAHCT Standards published

• 1997: First FACT inspections took place

• 1998: First programs awarded FAHCT accreditation

• 2000: FACT and NetCord partnered to develop cord blood standards and accreditation program

• 2001: Name changed to Foundation for the Accreditation of Cellular Therapy (FACT) to encompass cells beyond only HPC

• 2006: Began collaboration with JACIE on cellular therapy standards

FACT: Major Goals

• To promote quality patient care and quality laboratory performance• a valid accreditation process for cellular

therapy must review both

• Continue development of rapidly evolving field where major therapeutic advances continue to be made

Excellence in Cellular Therapy

• Requirement by health insurance companies, managed care organizations, and governments

• Resource for patients making health care decisions

• Regulatory compliance tool with cost savings

• Ranking measurement by US News & World Report

Support to Cellular Therapy Programs

• Collegial

• Dynamic and flexible to adapt to evolving needs

• Evidence-based Standards development every three years

• Updated guidance information as needed

• Comprehensive educational opportunities

• Assistance throughout the accreditation process and between cycles

• Dissemination of information from parent organizations

FACT Background

• 4 editions of the standards have been published, work underway on the 5th

edition.

• Cooperative International Standards for Cellular Therapy with JACIE (joint accreditation committee isct-ebmt)

• Volunteer peer inspectors who are active (or within 3 years) within the community.

FACT Background

• 3 year accreditation with an interim report

Bacterial Contamination

• D6.13 The Processing Facility shall monitor and document microbial contamination of cellular therapy products after processing, as specified in Standard Operating Procedures.• D6.13.1 The results of microbial

cultures shall be reviewed by the Processing Facility Director or designee in a timely manner

• D6.13.2 The recipient’s physician shall be notified in a timely manner of any positive microbial cultures

Bacterial Contamination Standards

• B4.9 The Quality Management Plan shall include, or summarize and reference, policies and procedures on the management of Cellular therapy product with positive microbial culture results that address at a minimum:

• B4.9.1 Notification of the recipient

• B4.9.2 Recipient follow-up and outcome analysis

• B4.9.3 Follow-up of the donor, if relevant

• B4.9.4 Reporting to regulatory agencies if appropriate (editorial comment: it IS)

Bacterial Contamination Standards

• C4.9 The Quality Managemetn Plan shall include, or summarize and reference, policies and procedures, on the management of cellular therapy products with posiive micrbial culture results that address at a minimum:

• C4.9.1 Notification of the recipient’s physician

• C4.9.2 Investigation of Cause

• C4.9.2 Follow-up of the donor, if relevant

What is the common flow of such a product?

• Cultures obtained before and after processing (only the latter required)

• Generally 12-36 hours later microbiology notifies the HCT laboratory

• The laboratory notifies the clinical service and blood cultures are drawn from the donor.

• Notify apheresis

• Product is labeled as biohazardous

• Product is considered to be in quarantine

• Product manufacturing folder is sealed in a red folder indicating need to report to FDA when infused.

Flow of Work At The Time of Product Order for Infusion

• At the time of ordering for infusion, primary physician is reminded of status, told of reporting that will be done, given the opportunity to administer antibiotics per clinical SOP and the duty to discuss with the recipient and document

• After infusion blood cultures are monitored and status is followed throughout transplant.

Reporting of Product Infusion

• Designated individual from the Quality Unit in Transfusion Medicine reports the product infusion to the appropriate body (FDA).

Methodology

Collate citations from all 4th edition inspections

Identify the most commonly cited sections in Clinical, Collection, and Processing

Drill down into each of those sections

16

Program Characteristics

• 44 programs• Clinical Programs: 33

• Apheresis Collection Facilities: 32

• Marrow Collection Facilities: 12

• Processing Facilities: 33

• Accreditation cycles• Initial: 5

• First renewal: 10

• Second renewal: 14

• Third renewal: 1517

Aggregate Number of Citations

18Clinical Apheresis Marrow Processing

180191

22

240

Clinical Citations

19

B638%

B423%

B515%

B98%

B77%

B37%

Other2%

Donor Citations in Clinical Inspections

• Donor information and consent to donate

• Missing information related to the collection procedure

• Audit consent forms for compliance to B6.2.1

• If information is provided verbally, document everything in notes

• Advance authorization to release information

• New requirement in 4th edition

• Consent prior to notifying recipient of abnormal results

• Needs documentation

20

Donor Citations in Clinical Inspections

• Donor safety• Policy for follow-up of donors

• New requirement in 4th edition

• The policy is often missing – ensure all SOPs are updated and/or created to be in compliance with new requirements

• Issues of donor health communicated in writing to Collection Facility• Inspectors often cannot find this communication

• Flag documentation for inspector

• Use forms21

Quality Management Citations in Clinical Inspections

• Audits

• A timetable, or schedule, is required

• Schedule actual dates for audits each year

• Include provisions for ad hoc audits

• Focus on areas that have most impact on patient safety

• Assign audits to personnel not directly involved in work

• Use results to implement improvement activities

22

Quality Management Citations in Clinical Inspections

• Microbial cultures• Positive cultures must be reported to

recipient• Include in urgent medical need process

• If found after administration, report at same time as you report to the applicable governmental agency

• Errors, accidents, suspected adverse events, biological product deviations, and complaints• Need documentation individually and

cumulatively

• Pre-approve planned deviations

23

Standard Operating Procedure Citations in Clinical Inspections

• Staff review and training need to be documented for evidence of compliance

• Have employees sign attendance sheets and/or training forms at the time of review and training

• Ensure documentation is available to inspector

• SOP for SOPs needs to be thorough and current• Include each step listed in B5.2.1 and each element

required in B5.3

• Audit SOPs for compliance to the SOP for SOPs

• All required elements need to be in each SOP as applicable

• Audit for elements in B5.2 and B5.3

24

View the SOP for SOPs tutorial!

www.factwebsite.org

Collection Citations

25

C431%

C717%

C517%

C812%

C210%

C67%

Other6%

C827%

C527%

C423%

C714%

Other9%

Apheresis Marrow

Quality Management Citations in Apheresis Collection Inspections

• Description of minimal trainer qualifications

• Needs to be included, or summarized and referenced, in the QM Plan

• If included in QM Plan appropriately, inspector should be able to find the documentation

• Description needs to be adequate

• Describe what the minimal qualifications are as determined by the facility

26

Quality Management Citations in Collection Inspections

• Audits

• No evidence of audits being conducted

• Need to perform at a minimum the required audits listed in the Standards

• Document audits and make available to the inspector

• Lack of timetable

• Lack of analysis to identify improvement opportunities

27

Standard Operating Procedure Citations in Apheresis Collection

Inspections

• Release and exceptional release• Definition of release is commonly

misunderstood

• Release as defined by FACT applies to Collection Facilities: removal of product from quarantine or in-process status when it meets specified criteria

• Procedure often does not exist because Collection Facilities feel it does not pertain to them• Products “released” from the Collection Facility to

the Processing Facility must meet specified criteria as defined by the Collection Facility

28

Labeling Citations in Apheresis Collection

Inspections

• Label content must follow Appendices I and II• Ensure applicable SOPs meet the requirements

• Audit the labeling procedure against the tables

• Create forms and templates based upon the tables

• Adequately train personnel on the procedure

• Be sure label information matches actual practices

• Example: Recommended storage temperatures should match storage temperatures in use by the facility

• Use ISBT 128 as a resource

• Proper names are required

• Templates can be useful

29

Processing Citations

30

D428%

D214%

D712%

D910%

D510%

D610%

D107%

D85%

Other4%

Quality Management Citations in Processing Inspections

• Positive microbial culture results• Include, or summarize and reference, such

results in the QM Plan• Be sure all required elements are addressed

• Be specific

• If treated as a variance:• The procedures must specify this

• All required elements in D4.9 must be included

• Perform procedure adequately• Superficial investigation, documentation, and

reporting does not address the problem

31

Quality Management Citations in Processing Inspections

• Validation• Must be included, or summarized or

referenced, in the QM Plan

• Even if a procedure has been in use for years, it still needs to be validated and/or verified

• Documentation must be available to the inspector

• Review and acceptance of validation studies must be documented by appropriate individual from Quality Management

32

Processing Facility Citations in Processing Inspections

• Safety• Liquid nitrogen concerns:

• Coolers instead of dry shippers used during transport contain free-flowing liquid nitrogen

• Lack of goggles when looking into a liquid nitrogen tank

• No oxygen monitors in confined spaces with liquid nitrogen

• Fire concerns:

• Clearance between the ceiling and shelving appeared insufficient

• Other General concerns• Example: Raised flooring

33

Processing Facility Citations in Processing Inspections

• Facility cleaning and sanitation must be documented

• Even if hospital staff performs this function, it must still be documented

• Be sure the documentation is available to the inspector

• A procedure is required; this procedure should outline how the documentation is created and maintained

34

Labeling Citations in Processing Inspections

35

• Label content must follow Appendices I and II

–Ensure applicable SOPs meet the requirements

• Audit the labeling procedure against the tables

• Create forms and templates based upon the tables

• Adequately train personnel on the procedure

–Label information must match actual practice

• Example: Recommended storage temperatures should match storage temperatures in use by the facility

–UseISBT 128 as a resource

• Proper names are required

• Templates can be useful

– Label Version Control