1. Submission and Review of Preparation Process Dossiers

2. Overview When to submit a PPD Overview of Submission Procedure Overview of Review Procedure Questions

3. PPD Submission

4. When to submit a PPD New process New licence including processing Change in processing PPDs should be authorised before undertaking processing activity

5. http://www.hta.gov.uk/licensingandinspections/licensingunderthequalityandsafetyregulations/authorisingprocesses.cfm How to submit a PPD Basic Information FAQs Guide PPD

6. The Preparation Process Dossier A. Establishment Information B. General Information C. Reagents and Materials D. Quality Control Testing E. Process Validation F. Final Labelling/Accompanying Information G. Additional Information H. Declaration by DI

7. Descriptive Title The cryopreservation of neutrophils for human application A description of the tissues and cells Neutrophils collected from healthy adult donors Any donor selection criteria & non-mandatory testing requirements 18-30 years of age Liver function tests QC requirements Free from monocyte contamination 20 x10 6 cells/vial Negative fungal screen Details of the process SOP, flowcharts and representative processing worksheets

8. All reagents and materials that come into contact with tissues and cells e.g. PBS, DMSO, culture media, plasticware Should not present a risk to Q&S of processed cells CE marked: yes or no? Rationale/RA for choice of non CE marked reagents/kits

9. Quality Control Testing-samples taken over the course of processing What critical quality attributes (CQAs) are measured – by validated or CE marked tests What is the assay e.g. cell viability testing kit Is assay CE marked Criteria for release e.g. >80% viability What is being measured/output e.g. number of viable cells in the final product

11. Identify the Critical Quality Attributes (CQAs) Demonstrate that processing has not rendered the tissue harmful or clinically ineffective Examples of CQAs include: Corneas- density of viable cells per surface area Femoral heads- free from microbiological contamination PBSC- viability upon recovery Heart valves- size

12. Identify the Critical Processing Parameters (CPPs) Conditions that bring about or preserve the CQAs Examples of CPPs include: When freeze-drying acellular pericardium the CPPs of temperature and duration of the process have a critical impact on the CQAs of residual water and stability of the resulting collagen matrix For the controlled rate freezing of PBSC the CPP of cryoprotectant concentration has a critical impact on the CQA of viable cell recovery

13. A process optimisation report specifying the CPPs, how they were optimised and, where necessary, how their tolerance levels have been set A description of the CQAs, how they are to be assessed, and the acceptable result thresholds A validation plan with documented methodology All results obtained, in a clear form with relevant interpretation showing how at least three independent runs have produced tissues or cells within predetermined criteria for CQAs

14. At least 3 independent processing runs that meet predefined criteria, validation data Data presented as for publication Raw data may be requested at a later stage if required Run Number ABCD 0.020.0190.0390.022 0.0990.010.0610.013 0.030.0280.050.009 OUTPUT A B C D Comparative phenotype data (4 runs repeated 3 times) RUN NUMBER

15. Unique identifier Tissue Establishment Type of tissue/cells Requirement for labelling for distribution to end users P.159-162 Guide to Quality and Safety Assurance for Human Tissues and Cells for Patient Treatment Expiry Date Storage

16. PPD Submission Checklist Completed PPDs can be sent to: enquiries@hta.gov.uk HTA, 151 Buckingham Palace Road, London SW1W9SZ

17. PPD Review

18. What is the PPD review process? PPD assigned to WG member PPD reviewed by WG member PPD review presented at WG meeting PPD authorised by PPDWG More information needed? Further information requested from establishment Further information submitted by establishment No Yes

19. Proposed Timeframe for Review The PPDWG will aim to reach a decision within 20 working days of receipt of the completed dossier or any additional information requested by the HTA. A ‘completed dossier’ is one in which all fields of the form have been completed appropriately and all relevant validation data to support the application has been supplied.

20. PPD Initial Review Is it complete?

21. Inspection reports CAPAs Conditions Existing Activities Other PPDs Annual activity data SAEARs DI/LH information Relationship to the process Premises/Facilities Specific requirements: clean room, environmental monitoring

22. General Information SOP/description of process Specific Requirements Demonstrate Critical Quality Attributes Flowchart of preparation process Is the process clearly described? Are all the steps in the process necessary? Are samples taken for quality control testing?

23. In house/lower grade reagents used? Justification for use Standard raised to acceptable limit by additional testing? Are all critical reagents and materials included? Is all the required information provided? + additional testing

24. QC Testing - Samples taken over the course of processing What CQAs are measured – by validated or CE marked tests For example: Sterility testing-in process samples and end product Final cell count Sample viability Residual water in freeze dried tissue Purity e.g. phenotype of cells

25. Optimisation report for each CPP e.g. DMSO tolerance during cryopreservation - concentration of cryoprotectant and duration of exposure prior to freezing Appropriate CQAs identified, including acceptable results thresholds? e.g. free from microbial contamination following open processing Validation plan with documented methodology Are assays CE marked or appropriately validated? a) By studies conducted at your own establishment

26. Results in a clear format with relevant interpretation a) By studies conducted at your own establishment How are results presented? At least 3 independent runs produce tissues and cells within predetermined CQAs Relevant interpretation Any non-conformances considered

27. All referenced publications attached Publications are relevant to the process Operational validation Can you reproduce the process? How will staff be trained in the process? Are reagents of equal specification or appropriately validated? Have any changes been made to the process? Validation of changes? b) By studies published by others

28. Clinical results from tissues and cells supplied by your establishment using well established processing procedures Number of tissues and cells implanted following processing by your method Period over which these implantations occurred Procedures for reporting adverse reactions Context of the data if available National or worldwide success rates for the procedure c) By retrospective analysis of clinical results

29. Your PPD is now authorised You will receive written authorisation from a member of the PPD Working Group to undertake processing Licensing Standard GQ2d Processes affecting the quality and safety of tissues and/or cells are validated and undergo regular evaluation

30. Making changes to an existing process Change to existing process identified Notify the HTA Impact quality or safety of product? Managed by internal change control Submit change of process PPD YesNo Change control recorded

31. Summary Allow sufficient time for PPD review Check that appropriate information is provided Provide clear methodology and validation All CQAs and CPPs are clearly defined and supported by the validation report

32. For further information The HTA website: http://www.hta.gov.uk/licensingandinspections/licensingunderthequalityandsafetyregulations/authorisingtissueorcellpreparation processesfaqs.cfm http://www.hta.gov.uk/licensingandinspections/licensingunderthequalityandsafetyregulations/authorisingtissueorcellpreparation processesfaqs.cfm Enquiries helpline: 020 7269 1900 enquiries@hta.gov.uk Guidance Document: Preparation Process Dossiers – a guide for processors of tissues and cells for patient treatment

33. www.hta.gov.uk http://twitter.com/HTA_UK http://www.Facebook.com/HumanTissueAuthority