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Submission and Review of Preparation Process Dossiers
Overview
When to submit a PPD
Overview of Submission Procedure
Overview of Review Procedure
Questions
PPD Submission
When to submit a PPD
New process
New licence including processing
Change in processing
PPDs should be authorised before undertaking processing activity
http://www.hta.gov.uk/licensingandinspections/licensingunderthequalityandsafetyregulations/authorisingprocesses.cfm
How to submit a PPD
Basic Information
FAQs
Guide
PPD
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
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
Section B — preparation process — general information
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
Section C — Reagents and materials Reagent or material that comes into
contact with the tissues/cells
Specification
e.g. CE marked, clinical grade, reagent grade
etc.
Manufacturer or supplier product code
Quality Control Testing-samples taken over the course of processing What critical quality attributes (CQAs) are measured – by validated or CE marked tests
Section D — Quality control testing Test
(manufacturer name and
product code if applicable)
CE marked or validated? Description of
test article (analyte)
Criteria for release
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/outp
ute.g. number of viable cells in
the final product
Section E — Process validation
How have the processing methods applied been validated to demonstrate that they do not render the tissues clinically ineffective or harmful for the recipient?
a) By studies conducted at your establishment? YES NO If yes, please append a copy of the validation report.
b) By studies published by others? YES NO If yes, please append copies of the most relevant publications, and written verification that the process and the published process are equivalent.
c) By retrospective analysis of clinical results? YES NO If yes, please attach a summary of the analysis methods and results.
Section E — Process validation
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
Section E — Process validation
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
Section E — Process validation
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
Section E — Process validation
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
Section E — Process validation
Run Number
A B C D0.02 0.019 0.039 0.0220.099 0.01 0.061 0.0130.03 0.028 0.05 0.009
OU
TP
UT
A B C D
Comparative phenotype data (4 runs repeated 3 times)
RUN NUMBER
Section F — Final labelling and accompanying information
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
PPD Submission Checklist
Document Required? Included PPD SOP of the preparation process Process flowchart Reagent risk assessment and testing details Validation Report Your own validation Published studies by others Retrospective evaluation Sterilisation validation Viral inactivation validation Final labels Accompanying documents
Completed PPDs can be sent to: [email protected] HTA, 151 Buckingham Palace Road, London SW1W9SZ
PPD Review
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 informati
on needed?
Further information
requested from establishment
Further information
submitted by establishment
No
Yes
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.
PPD Initial Review
Is it complete?
Document Required? Included PPD SOP of the preparation process Process flowchart Reagent risk assessment and testing details Validation Report Your own validation Published studies by others Retrospective evaluation Sterilisation validation Viral inactivation validation Final labels Accompanying documents
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
Section A —Establishment Information
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?
Section B — preparation process — general information
In house/lower grade reagents used?
Justification for use Standard raised to acceptable
limit by additional testing?
Section C — Reagents and materials Reagent or material that comes into
contact with the tissues/cells
Specification
e.g. CE marked, clinical grade, reagent grade
etc.
Manufacturer or supplier product code
Are all critical
reagents and materials included?
Is all the required
information provided?
+ additional testing
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
Section D — Quality control testing Test
(manufacturer name and
product code if applicable)
CE marked or validated? Description of
test article (analyte)
Criteria for release
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?
Section E — Process validation
a) By studies conducted at your own establishment
Results in a clear format with relevant interpretation
Section E — Process validation
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
Figure 1. The effect of cryopreservation on cell viability. Cell viability was determined by trypan blue exclusion and was measured both pre and post cryopreservation for 10 independent batches of cells.
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?
Section E — Process validation
b) By studies published by others
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
Section E — Process validation
c) By retrospective analysis of clinical results
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
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
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
For further information
The HTA website: http://www.hta.gov.uk/licensingandinspections/licensingunderthequalityandsafetyregulations/authorisingtissueorcellpreparationprocessesfaqs.cfm
Enquiries helpline: 020 7269 1900
Guidance Document:
Preparation Process Dossiers – a guide for processors of tissues and cells for patient treatment
www.hta.gov.uk
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