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  2. I am not independent, I manufacture freezing bags • I am President of American Fluoroseal Corporation (Afc). • AFC has manufactured freezing bags since 1982. • AFC bags are marketed by CellGenix GmbH. • CellGenix GmbH is exhibiting Afc bags at this conference in the exhibit area. • This notice is required by ISCT and the Medical Education Collaborative.

  3. SOP for validation of freezing bags • The SOP presented here is on the ISCT website. It may be downloaded and used as a template for your validation work. • This SOP is also on my website: WWW.TOAFC.COM under FAQ. • The download is in WORD, it does not have these powerpoint notes.

  4. The SOP in ISO format 1.0 Purpose 2.0 Scope 3.0 Responsibility 4.0 References and Applicable Documents 5.0 Materials and Equipment 6.0 Health and Safety Considerations 7.0 Documentation Requirements 8.0 Definitions 9.0 Process—General Description 10.0 Process—Details 11.0 Other Pertinent Information 12.0 Training Requirements 13.0 Revision History 14.0 Attachments

  5. Title block of SOP • VALIDATION OF CRYOPRESERVATION BAGS • STANDARD OPERATING PROCEDURE # 126 Revision: __A___ • Director of Quality Assurance: ______________ Date: ______ • Director of Cryopreservation: ______________ Date: ______ • Effective date: _________________ • Next Review date: _________________

  6. Where to go for guidance

  7. Where do you get a validation protocol? • “The test conditions for (validation) runs should encompass upper and lower processing limits and circumstances, including those within standard operating procedures, which pose the greatest chance of process or product failure compared to ideal conditions.” • From Part IV, General Concepts, Guidelines on General Principles of Process Validation.

  8. FDA definition of Validation Protocol • A written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment, and decision points on what constitutes acceptable test results. • From Section III, Guideline on General Principles of Process Validation.

  9. FDA Elements of Process Validation • Tests and challenges should be repeated a sufficient number of times to assure reliable and meaningful results. • From Section VII, Elements of Process Validation, paragraph 1.

  10. 1. Purpose • This is a Standard Operating Procedure for validating cryopreservation bags and the process used for freezing, while frozen and during thawing. • (Note: In order to validate for cryopreservation, you must cryopreserve. This requires a Cryopreservation process.)

  11. 2. Scope…. • SCOPE: This Procedure includes selecting bags for validation, the validation process and the validation report. This procedure is used to determine whether the bag and can survive extreme conditions of processing. This will validate the bag, ports, overwrap, label, and all “in process devices, procedures and components”. Validation must challenge the limits of the procedure while using the same equipment, processes, and personnel that are used for routine processes. ….. More….

  12. 2. ….Scope • This procedure challenges the container by subjecting it to the lowest temperature that might be achieved in a laboratory setting. And the procedure challenges the integrity of the bag by both over filling and under filling. This procedure challenges the durability of the bag by extreme temperature shock. This procedure challenges the entire process by subjecting the product to ten sequential freeze thaw cycles. This procedure includes a form to report validation.

  13. Can’t I do a simple test? Drop Test

  14. Use your own SOPs • Validation must use the processes that your institution employs, and the processes must test the bags at the “worst case” conditions of your process. • Note: not the worst case you can think of.

  15. Durability test (worst case)

  16. How to validate • My bags sometimes fail when thawing because they inflate and crack. • Can I just use an inflation test?

  17. Can I validate the bags by inflating them until they break? Is inflation a part of your standard procedure? Pressure Testing

  18. Scope: There are testing labs • Can they do the validation for me?

  19. SCOPE • Can I send it out for validation? • Only if you send all your products to the same place for cryopreservation.

  20. No, you can’t send it out • Validation must be done by the same people who do the cryopreservation for the institution. They must use the same equipment and the same protocol that they use when freezing actual products.

  21. So, what is validation? • Process validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics. • From Section IV. General Concepts, Guideline on General Principles of Process Validation.

  22. 3. Who is Responsible • RESPONSIBILITY: Validation of cryopreservation bags is the responsibility of the Quality Assurance director who reports to the CEO of this institution. The Quality Assurance director must approve and sign this procedure. In the event that there is no Quality Assurance Director, a representative of management who reports to the chief executive officer or the chief executive officer may sign. The Cryopreservation Department Director also must approve and sign this procedure. It is the responsibility of the cryopreservation technical staff of this institution to carry out this procedure.

  23. 4. References • 21CFR820, sections A-H. • 21CFR820.75 Process Validation • 21CFR10.90 Guideline on General Principles of Process Validation. • 21CFR1271.230 Process Validation: “(a) General. Where the results of processing described in para 1271.220 cannot be fully verified by subsequent inspection and tests, you must validate and approve the process according to established procedures.” • FDA’s Guide to Inspections of Quality Systems Manual: QSIT, August 1999. Particularly Section “Production and Process Controls”, inspection point number 4 “If the results of the process reviewed cannot be fully verified, confirm that the process was validated by reviewing the validation study”. (Search the Web: FDA QSIT). • This institution’s SOPs relating to freezing of products. • NOTE: ISO any standards?

  24. ISO Standards? • I have not found ISO standards for cryopreservation or freezing.

  25. What about this ISO standard? • (ISO 11607:2003(E) “Packaging for terminally sterilized medical devices” Is not applicable.) • (Search the web: ISO CRYOPRESERVATION, or ISO FREEZING)

  26. 5. Materials and Equipment • 5.1. Bags • 5.2 Overwraps • 5.3. Cryopreservation media • 5.4. Red food dye (unless the freeze media is deep red). • 5.5. Sealer • 5.6. Controlled Rate Freezer • 5.7. Freezer • 5.8. Thawing Water Bath, 40 degrees Celsius.

  27. 6. Health and Safety Considerations • 6.1. Handling frozen materials can cause frost bite. • 6.2. Persons following this procedure must be trained in the safe use of cryopreservation equipment, freezers, controlled rate freezers, and water baths.

  28. 7. Documentation Requirements • 7.1. Validation requires a clear data set that documents the work done, the results of the work, the name of the person who did the work, and the date. • 7.2. Section 14 contains a worksheet for recording the results of this procedure. The worksheet must be signed and dated at the appropriate places. • 7.3. This SOP is maintained in the “Quality Policy Manual” and is reviewed at least annually, or whenever the materials or procedures change. • 7.4. The validation report is maintained in the Quality Manual under “Quality Systems Records” and is available for audit.

  29. 8. Definitions… • 8.0. “SOP” shall mean “Standard Operating Procedure”. • 8.1. “Procedure” and “Process” mean the same thing and are interchangeable. • 8.2. “Critical equipment” shall mean any equipment or process that meets the following criteria: (a). Equipment that would make a defective product if it were not use properly. (b). Equipment that has adjustments or settings that control its operation. (c). Equipment that would create a defect that would not be detected by visual observation or subsequent procedures. • 8.3. “Cryopreservation” shall mean freezing to some temperature below the solidification of the product. ...

  30. 8. ….Definitions • 8.4. “Filling” shall mean adding fluid to the bag to a volume indicated by this institution’s SOPs. If not otherwise specified filling will be to a thickness of 1.0 centimeters. • 8.5. Temperature and volume measurements shall be made in the International Metric units. • 8.6. “Water Bath” shall mean a container of water in which the water is maintained at 40 degrees Celsius. • 8.7. “Product” shall mean the bag, its contents, and any necessary accessories. • 8.8. “Overwrap” shall mean a bag or other covering that is placed over the product to wrap the product bag, contain any leaks, and protect the product from contamination. • 8.9. “this institution” shall mean the organization manufacturing the product and doing the validation. • 8.10. “Cryopreservation media” shall mean the fluids that normally would be used to fill the bag, not necessarily including any biologics.

  31. 9. Process – General Description… • Records for Critical Equipment are examined to ensure that the equipment is installed in a quality manner (IQ). Records for critical equipment are examined to ensure that it operates in a quality manner (OQ). Records for critical equipment are examined to see that proper maintenance has been done. Each of these records: IQ, OQ, and maintenance are recorded. Obtain and reference any instructions from the bag manufacturer regarding use of the bag.

  32. 9. …Process – General Description • Ten bags are filled using this institution’s cryopreservation media following the SOPs of this institution. The fill solution is supplemented with red food dye to permit easy visualization of any leak. The bags are frozen in a controlled rate freezer following this institution’s SOPs. The bags are transferred into liquid nitrogen overnight or longer as noted in the validation report. The bags are removed from liquid nitrogen and placed directly into a 40 degree water bath. The bags are observed for leaks into the water bath as evidenced by escape of red dye, readability of labels, and condition of ports and overwrap. Then the freeze thaw cycle is repeated nine more times with the same bags. The observations are recorded on the attached form.

  33. 10. Process – Details… • Obtain and review the IQ, OQ, and maintenance records for the controlled rate freezer and record the file numbers on the Validation Record form. • Obtain and review the IQ, OQ, and maintenance records for the freezer and record the file numbers on the Validation Record form. • Obtain and review the IQ, OQ, and maintenance records for the water bath and record the file numbers on the Validation Record form. • Select nine bags to be tested: These are taken from the top, middle, and bottom of the next 3 cases of product bags that would normally be used. • Record the manufacturer and lot numbers of the bags. • Mark the bags with sequential numbers using this institutions method.

  34. 10. …Process - Details • Add red food dye to the cryopreservation media to develop a deep red color (if the media is not already deep red). • Fill bags 1, 4, and 7 with the volume of fluid that this institution recommends. • Fill bags 2, 5, and 8 with twice the volume of fluid that this institution recommends. • Fill bags 3, 6, and 9 with half the volume of fluid that this institution recommends. • Freeze the bags in the controlled rate freezer to -80 degrees Celsius according to this institution’s procedure. • Transfer the bags to the liquid phase of a liquid nitrogen freezer. • Store overnight or over weekend. • Remove bags from the freezer and place directly into 40 degree Celsius water bath. • Observe for leakage of fluid. Report any leakage as “leak”. • Observe for loss of protective cover over port. Report cover loss as “cover lost” • Observe for ability to read bag identity information. Report inability to read as: “loss of identity”. • Observe for breaks in the overwrap. Report as “overwrap failure”. • Sign and date each entry. • Remove any bags that leak or otherwise fail from the validation cycle. • Repeat the freeze and thaw process for 10 cycles. • Submit to the Quality Assurance Director for conclusions. • Any failure invalidates the process.

  35. 11. Other Pertinent Information • In this section, include any information that relates to the validation process such as references that are not directly used. For example: literature on freezing. • In this section, include previous or other pertinent validation studies or notes.

  36. 12. Training Requirements • Technicians responsible for validation work shall read and be familiar with 21CFR820. • Technicians responsible for validation shall complete Cryopreservation training as required by this institution. • Quality Assurance shall train technicians in this procedure and shall properly note training in the employees training record.

  37. 13. Revision History • This revision (A) is given as an example of how to make and record a revision to the procedure. • Food Color dye was added to the procedure. The reason for the change is that it was noted that after several freezes, the dye in the cryopreservation media becomes pale and harder to see. Changes were made to section 5, 9, and 10. No other changes were made. The revision level was changed from 0 to A. Changes made by John Jones, April 4, 2006.

  38. Attachments • RECORDS: • Freezer IQ record number: _______ • Freezer OQ record number: _______ • Freezer Maintenance record number: _______ • Controlled rate freezer IQ: _______ • Controlled rate freezer OQ: _______ • Controlled rate freezer Maintenance record number: _________ • Water Bath IQ record number: _______ • Water Bath OQ record number: _______ • Water Bath Maintenance record number: ___________ • Bag Manufacturer: _______________________________ • Bag Lot Numbers: ________________________________ • Training record of person doing Validation procedure: __________ • This is the data taken of 10 freeze/thaw cycles: • Cycle results Date Signed • 1. _______________ _____ _______ • 2. _______________ _____ _______ • 3. _______________ _____ _______ • 4. _______________ _____ _______ • 5. _______________ _____ _______ • 6. _______________ _____ _______ • 7. _______________ _____ _______ • 8. _______________ _____ _______ • 9. _______________ _____ _______ • 10. _______________ _____ _______ • Review by Quality Assurance, Signed: _________ date: _________ • Conclusion: _________________________________ • _____________________________________________ • End of SOP # 126 rev A