Authorising tissue or cell preparation processes
It is a mandatory requirement that the processes that are used to prepare tissue or cells for human application do not render them clinically ineffective or harmful, and they must be validated. The validation of the processes may be based on:
- An establishment’s own studies;
- Data from studies published by others with operational validation; or
- A retrospective analysis of clinical outcomes.
The HTA has adopted the Preparation Process Dossier (PPD), as recommended by the European Commission, to assist its review of process validation. We may ask you to complete a PPD for each process you use. It includes information regarding process validation, reagents and materials, quality control and labelling; a template is available (Word). In addition, we provide guidance on completing the PPD template (PDF).
Prior to the introduction of PPDs, we found significant variability in establishments understanding of what is required to validate preparation processes satisfactorily. The PPD aids clarity as it sets out a format for the information you will need to collect, and will help you fill any gaps in your validation. The common format contributes to ensuring that the HTA’s review process is conducted efficiently and consistently.
New licence applications for processing of tissue or cells for human application must include a PPD to describe the process validation. Processing of the tissues and cells cannot commence until the processes proposed under a new licence have been authorised. We also require new or modified processes to be authorised. It is a standard condition on all licences that you inform the HTA of any change to your activities. If the changes to your preparation processes might have an impact on the quality or safety of the tissues or cells, then you will be asked to complete a PPD.
We may ask establishments licensed for processing under the Human Tissue (Quality and Safety for Human Application) Regulations 2007 to complete a PPD prior to a scheduled site-visit inspection, if the processes have not already been authorised through the PPD process. A PPD will generally not be requested if validation of routine and well established processes has been recorded by the HTA during previous inspections.
Licensing standard GQ2d requires that ‘Processes affecting the quality and safety of tissues and/or cells are validated and undergo regular evaluation’. You may be asked to submit a PPD if a shortfall is recorded against this standard during a site visit inspection.
As the name implies, PPDs refer only to preparation processes. Procedures used to procure, distribute, store or engraft tissues or cells fall outside the scope of PPDs. Preparation processes include all operations involved in the preparation, manipulation, preservation and packaging of tissues or cells intended for human application. Preparation processes do not include activities such as the washing of femoral heads during procurement in an operating theatre.
In general, packaging and labelling of tissues or cells should be regarded as a stage in the preparation process. There is a specific section of the PPD for you to record labelling and accompanying documentation that must be completed if you are distributing tissues or cells for end use.
In some cases, tissues and cells used as starting materials for biological medicinal products are processed by establishments under the Human Tissue (Quality and Safety for Human Application) Regulations 2007. One example of this is the processing activity that is carried out to derive early cell lines or banks, prior to establishing a Master Cell Bank. In these cases, you will be required to submit a PPD to the HTA to cover this early stage processing.
An ATMP (MP or IMP) may contain, or consist of, cells or tissues that have either been subject to ‘substantial manipulation’, or that will not be used for the same essential function(s) in the recipient as in the donor. Under these circumstances, the HTA will regulate the donation, procurement and testing of human tissues and cells. The MHRA will regulate the manufacture, storage and distribution of these products. One example of this is chondrocyte procurement for use in Matrix Induced Chondrocyte Implantation (MACI).
All PPD submissions are reviewed by the PPD Working Group (PPDWG). Your PPD will be assigned to a Regulation Manager from the PPDWG, who will be your HTA contact throughout the authorisation process. This PPDWG member will review your submission and then present it for consideration at a PPDWG meeting. If the PPDWG require further information, you will receive an email from your PPDWG contact outlining this. Once you have submitted further information, this will be reviewed using the same process.
We aim to reach a decision on complete PPD submissions within 20 working days of receipt. The approval process may be extended if your submission is incomplete, or if we require further information.
Where the PPDWG decide that additional information is needed (e.g. further validation studies, submission of additional published data, etc), PPDs will be deemed ‘incomplete’ and you will be informed of this decision within 20 working days. In these cases, the timeline for a decision on the status of your PPD will restart once you have submitted the additional information.
>PPDs should be authorised by the HTA before you undertake any processing activity. If there is an urgent need for you to begin processing any tissues and cells, then you should inform the HTA at the point of submission.
Section G on the PPD form provides a space for you to include additional information that the HTA should be aware of with respect to the reviewing and authorisation of your preparation process. For example if there is an urgent clinical need for the tissues or cells covered by the PPD then this should be indicated within this section.
At the point that your PPD is authorised, you will receive written confirmation from the PPDWG. An authorised preparation process is one which has passed the HTA’s internal due diligence process and for which documentation has been provided by the establishment to demonstrate compliance with the requirements of the EU Tissue and Cells Directive 2006/86/EC Article 4 and Annex II Part B.
Processes affecting the quality and safety of tissues and cells should undergo regular evaluation to ensure they continue to achieve the intended results. Directions given by the HTA in relation to these requirements are set out in the HTA’s licensing standards and evidence of compliance may be sought as part of any future inspection.
The authorisation of a preparation process by the HTA does not extend to authorisation of the end use of the tissue or cells. This is a clinical decision which should take into account all relevant scientific and clinical information. The HTA is satisfied that the preparation process does not render the tissues or cells clinically ineffective or harmful to the recipient, but does not have the remit to provide any regulatory assurance that the end use will be of benefit or clinically effective. As such, no tissue establishment may seek to rely on an HTA authorisation of a PPD as providing any such assurance.
The PPD was an outcome of the European Standards and Training in the Inspection of Tissue Establishments (EUSTITE) project, in which EU Member States and the World Health Organisation recommended its use for the authorisation of processing of tissues and cells. The project included consultation across Europe. Competent Authorities, like the HTA, are expected to implement PPDs after the European Commission decided to adopt this recommendation.
The HTA introduced the PPD following development with stakeholders in the sector. A series of pilots were conducted as part of routine inspections in a six-month period of the 2011/12 year, during which feedback was sought and improvements were made to make the PPD clearer.
In May 2013, the HTA held a workshop on PPDs which was attended by 35 delegates from establishments across the UK that process human tissues or cells for human application. The workshop included presentations by members of the HTA’s PPDWG on the regulatory background to PPDs and the PPD submission and review process.
Workshop attendees also participated in a series of interactive sessions. These aimed to provide clarification on the information that should be submitted to the HTA to evidence the validation of preparation processes, and the occasions when it is necessary for organisations to provide such information.
Presentations from the workshop are available on the HTA website. Further information on how to write a PPD is available in our guidance document (PDF). If you have any questions about writing a PPD, please contact the HTA by telephoning 0207 269 1900 and ask to talk to a member of the PPDWG.
Tissue establishments are required to demonstrate that critical tissue and cell processing procedures have been validated to ensure that they do not render the tissues or cells clinically ineffective or harmful to the recipient/patient. There is no requirement for studies demonstrating clinical effectiveness.
If, however, you choose to base the validation of your processes on a retrospective analysis of clinical outcomes, demonstration of clinical efficacy and safety of the tissues/cells may be used to provide evidence of validation.
If you are conducting your own validation studies, your preparation process must be shown to deliver tissues or cells with the required properties (Critical Quality Attributes; CQAs) that are necessary to ensure they are not clinically ineffective or harmful. You will define these CQAs depending on the tissues or cells in question, and their function during human application.
Critical Quality Attributes (CQAs) demonstrate that processing has not rendered the tissue harmful or clinically ineffective. Some examples of CQAs include: sterility (in both processed samples and in the end product); final cell count; sample viability; residual water in freeze dried tissue; and purity (e.g. phenotype of cells).
Critical Processing Parameters (CPPs) are the conditions that bring about or preserve the CQAs. For example, 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.
When an establishment is looking to undertake a preparation process that has been established elsewhere, you may be able to use previously published data to evidence that your processing method does not render the cells harmful or clinically ineffective. In such instances, you should submit evidence of how the preparation process will be implemented to equivalent standards in your own facility.
In situations where suitable material is not available for validation purposes only, we would look to authorise the PPD on the basis of the alternative steps the establishment has taken to ensure the quality and safety of the tissues / cells during the preparation process.
For example, this could be through the submission of information that demonstrates that the establishment will use well-established protocols/reagents/equipment.
Where protocols are being transferred from one lab to another, we would look for evidence of training by those experienced in carrying out the technique, and evidence of supervision during the early implementation phase at the new premises.
We would also look for evidence that the establishment has put in place appropriate quality control checks. In line with this, we would expect establishments to have clear release procedures in place to ensure that samples are not released for clinical use unless the processing has achieved well-defined quality and safety criteria.
We would additionally expect the establishment to clearly map out how they intend to review the data from the initial processing runs, as part of their on-going operational validation. In situations such as this, our expectation is that this information will be submitted to the HTA for review at the earliest opportunity.
An assessment will be made by the HTA on a case per case basis and will include a risk analysis encompassing clinical need.
If the change to an authorised process has the potential to affect the quality and safety of the tissues or cells, then you may be required to submit a PPD for this change of process. A member of the PPDWG will be able to advise you on whether a change of process PPD is required or whether the change can be managed by your own internal change control processes only.
The information that is submitted in PPDs will be treated by the HTA in confidence; we do not intend to publish PPDs or information extracted from these documents. This is particularly important for those establishments where the information has a commercial value.
Requests for information may be made under the Freedom of Information Act 2000. Where a request is made to the HTA, and where this relates to an establishment or a person, the HTA will contact that establishment to seek views on whether there are any concerns around release of information. These views are then used by the HTA to decide whether or not to release the information, and if not, the grounds on which it is withheld. Adopting this approach on a case by case basis means that views on what is and what is not to be regarded as commercial interests can be taken on each request.
Section 43 of the Act has two different qualified exemptions designed to protect commercial interests. The first regards class-based information, which is exempt if it constitutes a trade secret. The second is prejudice-based information, which is exempt if its disclosure under the Act would, or would be likely to, prejudice the commercial interests of any person or organisation.