The Peripheral Stem Cell Process and Directive 200423EC

The Peripheral Stem Cell Process and Directive 2004/23/EC D. Keane, Nov. 2005 1 Before We Start Your Glass is Half Full You are all Technical Experts D. Keane, Nov. 2005 2 Draw the Process Flow Diagram  Identify the inputs or steps in your process from assessment to transfusion.  Draw a Process Flow diagram.  Pay particular emphasis to control points.  The process in each tissue establishment is unique. D. Keane, Nov. 2005 3 Review the Process Flow Diagram  Review each input bearing in mind:Consequence of failure or non conformance Ability to detect the failure Frequency of failure D. Keane, Nov. 2005 4 The Process Flow Assessment Distribution Donation Storage Preservation Critical Control Points? D. Keane, Nov. 2005 Testing Acceptance 5 Output of the Process Flow Diagram  Output of your review:Detailed Process Flow Diagram Risk Assessment Starting point for defining your Quality System D. Keane, Nov. 2005 6 Process Flow and Quality Management System  These inputs constitute your Quality Management System in that you identify what needs to be:Managed Changed Reviewed on an ongoing basis. D. Keane, Nov. 2005 7 Next Step  Review your inputs  Draw up your Process Flow Your Process Flow is the starting point for your tissue establishment. D. Keane, Nov. 2005 8 Procurement  Procurement of peripheral stem cells incorporating: Donor assessment (non testing) Takes place  Testing within days  Donation This process may or may not take place at the tissue establishment. D. Keane, Nov. 2005 9 Processing  Processing of harvested peripheral stem cells incorporating:Storage Acceptance (Incoming Inspection) Preservation Labelling/ Batch Release Distribution Infusion/ Destruction This process normally takes place at the tissue establishment but some elements may be contracted out. D. Keane, Nov. 2005 10 Donor Assessment Donor assessment (non testing): Consent  Donor Identification  Donor Questionnaire Voluntary unpaid  Donor Interview donors. Refer to  Donor Medical History article 12.  Deferral Criteria  Clinical Sign-Off D. Keane, Nov. 2005 11 Donor Assessment  Consent  Must be documented  Witnessed  Consent applying to:- Donation - Transplantation/ Infusion - Research - Destruction (stockpile from deceased donors) D. Keane, Nov. 2005 12 Donor Assessment  Consent should - incorporate:Detailed explanation of process Explanatory leaflet Explanation of risks/ benefits Signatures D. Keane, Nov. 2005 13 Donor Assessment  Donor/Donation Identification (Traceability)  Define your requirements.  Acceptance of historical data.  Assigning a unique number to the donor.  Assigning a donation number to donations/ aliquots which is traceable to the donor number.  Procedure for positive ID of donor. D. Keane, Nov. 2005 14 Donor Assessment  Donor/Donation Identification (Traceability)  Policy for dealing with:- Twins - Donors with the same surname - Duplicate donor records - Policy on merging duplicates D. Keane, Nov. 2005 15 Donor Assessment  Donor Questionnaire Incorporating Medical Interview and History  Allogenic and Autologous  The questionnaire should:- Access eligibility of donor. - Each question will have defined criteria e.g. deferral guidelines. D. Keane, Nov. 2005 16 Donor Assessment  Clinical Sign-Off  Under supervision/ authority of the responsible person, there must be formal acceptance/ rejection of the potential donor. D. Keane, Nov. 2005 17 Donor Assessment  Documentation of the Process  How many documents  Review IBTS blood donor questionnaire and interview process:- Guidelines for donor referral - Questionnaire incorporating:- Donor identification - Blood donation details - Recent medical history D. Keane, Nov. 2005 18 Donor Assessment  Documentation of the Process - Questionnaire incorporating:- Detailed medical questions. - Results of medical assessment. - Medical interview details. - Consent. - Documentation of adverse events. - Authorisation to donate. D. Keane, Nov. 2005 19 Donor Assessment  Approval of the Assessment Process  Directive requires approval by the tissue establishment (responsible person). • Records  Retain all records (suitable/ unsuitable). D. Keane, Nov. 2005 20 Donation Donation Sample  Purpose – quantify stem cell harvest (acceptable range).  Volume of donation: Method of taking sample D. Keane, Nov. 2005 21 Donation Donation Sample  Perform testing (refer to points for consideration)  Records of calculations must be kept including records of double checks for manual calculations.  A report of the CD34 result is required for the production/ preservation processes. D. Keane, Nov. 2005 22 Donation Donation Process Control: Identification of the donor (positive ID)  The environment (safe and clean)  Design of the workflow from apheresis set inspection to labelling and transport of donation to the tissue establishment.  Critical materials (in process inspection) D. Keane, Nov. 2005 23 Donation Donation Process Control: Reporting of defective materials as per invitro diagnostic device directive  Traceability of all equipment and materials used in the collection process:- Apheresis equipment (asset no.) - Stem cell apheresis sets (lot no., expiry) - Plasma bag (lot no., expiry) - anticoagulant solution (lot no., expiry) D. Keane, Nov. 2005 24 Donation Donation Process Control: Venipuncture site (disinfection) - Pre palpation - Post palpation  Application of local anesthetic  Adverse events:- Flow rate - Set defective - Patient events and reactions D. Keane, Nov. 2005 25 Donation Donation Process Control: Validation of the apheresis process for stem cell collection  Suitability of collection site:- Cross contamination - Line clearance  Maximum extra corporal blood volume should not be exceeded during the apheresis process. D. Keane, Nov. 2005 26 Donation Donation Process Control: Packaging, labelling of the donation, samples and transport container.  Method of transport to the blood establishment D. Keane, Nov. 2005 27 Donation Documenting the donation process?  Using the same document as used for the assessment process  Development of a tissue donation record card The donation process documentation should accompany the donation and the samples to the tissue establishment. D. Keane, Nov. 2005 28 Donation  Approval of the Donation Process The tissue establishment should approve the donation process (responsible person). D. Keane, Nov. 2005 29 Testing  Testing  Pre donation testing  Post donation testing D. Keane, Nov. 2005 30 Testing  Testing (points for consideration)  Tests include:- CD34 Quantitation - HLA, ABO, RhD - Anti HCV - HBsAg - Anti HBc - Anti HIV-1,2 D. Keane, Nov. 2005 31 Testing  Testing (points for consideration)  Tests include:- Syphilus - FBC - NAT PCR testing (HIV/ HCV)  The testing laboratory should be approved by the competent authority and if contracted, a formal contract must be in place. D. Keane, Nov. 2005 32 Testing  Testing (points for consideration)  Reagents and test kits should be CE marked.  Test methods/ equipment must be validated to verify suitability for intended use.  The samples for serological tests should be validated to take account of Haemodilution. D. Keane, Nov. 2005 33 Testing  Testing (points for consideration)  A validated serum archive storage system should be in place for infectious markers:- Temperature mapping/ continuous monitoring - Minimum volume requirements  Repeat testing for infectious markers, where donation is still in storage. D. Keane, Nov. 2005 34 Testing  Testing (points for consideration)  The approved test methods should be in accordance with manufacturers instructions.  Test kits and control material should be approved for use in advance of usage. D. Keane, Nov. 2005 35 Testing  Testing (points for consideration)  For infectious markers require approved protocols for positive results.  The testing system, if automated and linked to the host computer system, should be validated for compliance with G.A.M.P. (Good Automated Manufacturing Process). D. Keane, Nov. 2005 36 Testing  Testing (points for consideration)  Staff must be appropriately qualified and trained to perform, review and report test results (training records).  Availability of and satisfactory performance with internal and external quality control programmes.  Test results form part of the donor records and ultimately the patient file of autologous donation. D. Keane, Nov. 2005 37 Testing  Testing (points for consideration)  Valid equipment control programmes incorporating PM, calibration, breakdown and repair, cleaning and availability of adequate back-up. D. Keane, Nov. 2005 38 Testing Pre Donation  Mobilization regime (bone marrow stimulation).  Screening for infectious markers.  Other tests. Donation  Donation sample (CD34 measurement) Post Donation  FBC (post infusion)  Compatibility testing D. Keane, Nov. 2005 39 Processing of Harvested Peripheral Stem Cells  Acceptance of the donation by the tissue establishment  Preservation  Storage  Distribution D. Keane, Nov. 2005 40 Acceptance of Harvested Peripheral Stem Cells  Need a detailed procedure outlining the inspection process:- Document review (tissue donation record card) - Transportation review - Packaging and labelling review Acceptance criteria should be defined. D. Keane, Nov. 2005 41 Acceptance of Harvested Peripheral Stem Cells  Need a procedure defining the tissue donation registration process (electronic/ manual).  The status of the donation should be clearly identified as in process.  Record date/ time received into the laboratory into the tissue establishment. D. Keane, Nov. 2005 42 Acceptance of Harvested Peripheral Stem Cells  Prior to donation and acceptance, it may be appropriate that the tissue establishment has master documentation for:- Consent - The donor questionnaire - The donor interview - Test results D. Keane, Nov. 2005 43 Acceptance of Harvested Peripheral Stem Cells  A documented checklist may be useful to release the donation to processing/ production. D. Keane, Nov. 2005 44 Preservation Controlled Environment (if required)  Room design  Room classification/ specification  Control of personnel  Routine environmental monitoring  Preventative maintenance D. Keane, Nov. 2005 45 Preservation Controlled Environment (if required)  Layout drawing – locations for monitoring  Frequency of monitoring:- Depends on grade of room - Criticality of operation - Grade A operation monitor each time  Corrective action in the event of non conformity. D. Keane, Nov. 2005 46 Preservation Controlled Environment (if required)  Air handling units  Filter integrity checks  Leak tests D. Keane, Nov. 2005 47 Preservation Preparation for Cryopreservation  The dose or quantity of peripheral stem cells is known.  Decision made on how many therapeutic doses to be preserved from the original donation.  Need to perform calculations that give a therapeutic dose. D. Keane, Nov. 2005 48 Preservation Preparation for Cryopreservation Plasma for reconstitution with D.M.S.O.:- Storage at 4ºC - Addition of D.M.S.O. plasma mixture to the donation. - Open or closed system for reconstitution (SCD). D. Keane, Nov. 2005 49 Preservation Preparation for Cryopreservation  D.M.S.O. is toxic to peripheral stem cells at a defined temperature.  The mixture must be transferred to a cryogenic bag (open or closed). D. Keane, Nov. 2005 50 Preservation Preparation for Cryopreservation  What do we need to control? - Air quality (Grade A Laminar Flow Activity) - Time between donation and cryopreservation - Temperature of final mixture - Homogenity of final mixture (at cryopreservation) D. Keane, Nov. 2005 51 Preservation Preparation for Cryopreservation  What do we need to control? - Sterile connecting devices - The labelling and suitability of cryogenic bag system - D.M.S.O. (Dimethylsulphoxide)  Liquid nitrogen (coolant) uses:- Control rate freezing - Storage of preserved donations D. Keane, Nov. 2005 52 Preservation Control Rate Freezing  Validated cryogenic freezer (time/ temperature).  Verify each run using QC bag with equivalent matrix and volume (batch release).  Control freezing rate especially at eutectic point. D. Keane, Nov. 2005 53 Preservation Control Rate Freezing  Establish eutectic range with your process parameters and set up freezing protocol to match.  The freezing process must preserve:- Labelling - Cryogenic bag - Peripheral stem cells D. Keane, Nov. 2005 54 Storage  Define maximum storage period with justification.  Segregation:- Allogenic - Autologous - Deceased - Research/ Validation - Rejected D. Keane, Nov. 2005 55 Storage  Inventory control and reconciliation.  Continuous temperature monitoring.  Continuous liquid N2 monitoring:- Level - Flow rate D. Keane, Nov. 2005 56 Distribution Release of Tissue  Have a procedure for releasing tissue:- Collection data - Donation data - Testing data - Incoming inspection and acceptance data - Clean room monitoring data D. Keane, Nov. 2005 57 Distribution Release of Tissue  Have a procedure for releasing tissue:- Freeze curve - Liquid nitrogen monitoring data  Who formally releases the tissue? Is the release documented? D. Keane, Nov. 2005 58 Distribution  Thawing - Pre-thawing control - Thawing control  Pre-Thawing - Request for infusion. How? - Matching of allogenic processed stem cells to potential recipients. D. Keane, Nov. 2005 59 Distribution  Pre-Thawing - How is the match authorised or rejected and where is it recorded? What testing is performed? How is the testing controlled?  Thawing - Method Type Waterbath Convection (dry heat) D. Keane, Nov. 2005 60 Distribution At 2 – 6ºC during transport and infusion.  ? Requirement for a validated transport system.  Trained staff.  Product recall procedure.  Traceability and look back.  Valid inventory and distribution records (despatch dockets).  D. Keane, Nov. 2005 61 Distribution  Labelling the product? (refer to blood components).  Labelling the shipping container? (refer to blood components). D. Keane, Nov. 2005 62