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
How to submit a PPD
Basic
Information
FAQs
Guide
PPD
http://www.hta.gov.uk/licensingandinspections/licensingunderthequalityandsafetyregulations/authorisingprocesses.cfm
The Preparation Process Dossier
A.
B.
C.
D.
E.
F.
G.
H.
Establishment Information
General Information
Reagents and Materials
Quality Control Testing
Process Validation
Final Labelling/Accompanying
Information
Additional Information
Declaration by DI
Section B — preparation process — general information
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Descriptive Title

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A description of the tissues and cells


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18-30 years of age
Liver function tests
QC requirements
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Neutrophils collected from healthy adult donors
Any donor selection criteria & non-mandatory testing
requirements

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The cryopreservation of neutrophils for human application
Free from monocyte contamination
20 x106 cells/vial
Negative fungal screen
Details of the process

SOP, flowcharts and representative processing worksheets
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
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 D — Quality control testing
Test
(manufacturer
name and
product code if
applicable)
What is the
assay
e.g. cell
viability
testing kit

CE marked or validated?
Is assay CE
marked
Description of
test article
(analyte)
What is being
measured/output
e.g. number of
viable cells in the
final product
Criteria for release
Criteria for
release
e.g. >80%
viability
Quality Control Testing-samples taken over the course of processing

What critical quality attributes (CQAs) are measured – by validated or CE marked tests
Section E — Process validation
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 
If yes, please append a copy of the validation report.
NO 
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
Comparative phenotype data
(4 runs repeated 3 times)
OUTPUT
Run Number
A
B
C
D
A
0.02
0.099
0.03
B
0.019
0.01
0.028
C
0.039
0.061
0.05
D
0.022
0.013
0.009
RUN NUMBER

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 F — Final labelling and accompanying information
Tissue
Establishment
Unique identifier
Type of tissue/cells
Storage
Expiry Date
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
PPD Submission Checklist
Document
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
Required?
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Included

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Completed PPDs can be sent to:


enquiries@hta.gov.uk
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
Further information
submitted by
establishment
More
information
needed?
Further information
requested from
establishment
Yes
No
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
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
Required?




Included











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Section A —Establishment Information

Inspection reports



Existing Activities




Other PPDs
Annual activity data
SAEARs
DI/LH information


CAPAs
Conditions
Relationship to the process
Premises/Facilities

Specific requirements: clean room, environmental monitoring
Section B — preparation process — general 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 C — Reagents and materials
Reagent or
material that
comes into
contact with the
tissues/cells
Are all critical
reagents and
materials
included?
Specification
e.g. CE marked, clinical
grade, reagent grade
etc.
Manufacturer or
supplier
In house/lower grade reagents
used?


Justification for use
Standard raised to acceptable
limit by additional testing?
+
additional
testing
product code
Is all the
required
information
provided?
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
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 E — Process validation
a) By studies conducted at your own establishment

Optimisation report for each CPP


Appropriate CQAs identified, including acceptable results
thresholds?


e.g. DMSO tolerance during cryopreservation - concentration of
cryoprotectant and duration of exposure prior to freezing
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
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.

How are results presented?

At least 3 independent runs
produce tissues and cells
within predetermined CQAs

Relevant interpretation
 Any non-conformances
considered
Section E — Process validation
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?
Section E — Process validation
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
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
Managed by
internal change
control
Change control
recorded
No
Impact
quality or
safety of
product?
Yes
Submit change of
process PPD
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



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/authorisingtissueorcellpreparation
processesfaqs.cfm

Enquiries helpline: 020 7269 1900
enquiries@hta.gov.uk
www.hta.gov.uk
http://twitter.com/HTA_UK
http://www.Facebook.com/HumanTissueAuthority