VALIDATION of FREEZING BAGS

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VALIDATION of FREEZING BAGS

• AN SOP

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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.

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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.

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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 ProcessGeneral Description
• 10.0 ProcessDetails
• 11.0 Other Pertinent Information
• 12.0 Training Requirements
• 13.0 Revision History
• 14.0 Attachments

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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 _________________

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Where to go for guidance
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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.
  http//www.fda.gov/cder/guidance/pv.htm

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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.

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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. http//www.fda.gov/cder/guidance/pv.
  htm

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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.)

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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.

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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.

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Drop Test

• Cant I do a simple test?

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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.

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Durability test (worst case)
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How to validate

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

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Pressure Testing

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

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Scope There are testing labs

• Can they do the validation for me?

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SCOPE

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

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No, you cant 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.

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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.
  http//www.fda.gov/cder/guidance/pv.htm

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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.

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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.
• FDAs 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 institutions SOPs relating to freezing of
  products.
• NOTE ISO any standards?

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ISO Standards?

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

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What about this ISO standard?

• (ISO 116072003(E) Packaging for terminally
  sterilized medical devices Is not applicable.)
• (Search the web ISO CRYOPRESERVATION, or ISO
  FREEZING)

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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.

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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.

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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.

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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. ...

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8. .Definitions

• 8.4. Filling shall mean adding fluid to the bag
  to a volume indicated by this institutions 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.

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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.

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9. Process General Description

• Ten bags are filled using this institutions
  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 institutions 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.

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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.

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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
  institutions 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.

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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.

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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.

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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.

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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. _______________ _____
  _______

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