Submission and Review of Preparation Process Dossiers

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

6. The Preparation Process Dossier • Establishment Information • General Information • Reagents and Materials • Quality Control Testing • Process Validation • Final Labelling/Accompanying Information • Additional Information • 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 x106 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 markedtests What is the assay e.g. cell viability testing kit Is assay CE marked What is being measured/output e.g. number of viable cells in the final product Criteria for release e.g. >80% viability

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. Comparative phenotype data (4 runs repeated 3 times) • 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 OUTPUT A B C D RUN NUMBER

15. Tissue Establishment 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 Unique identifier Type of tissue/cells Storage Expiry Date

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 Further information submitted by establishment More information needed? No Further information requested from establishment 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? Is all the required information provided? Are all critical reagents and materials included? + 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. a) By studies conducted at your own establishment • 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?

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

27. b) By studies published by others • 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?

28. c) By retrospective analysis of clinical results • 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

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 existingprocess identified Notify the HTA Impact quality or safety of product? No Yes Managed by internal change control Submit change of process PPD 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 • Guidance Document: • Preparation Process Dossiers – a guide for processors of tissues and cells for patient treatment • The HTA website: http://www.hta.gov.uk/licensingandinspections/licensingunderthequalityandsafetyregulations/authorisingtissueorcellpreparationprocessesfaqs.cfm • Enquiries helpline: 020 7269 1900 enquiries@hta.gov.uk

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